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Zhang S, Wen Q, Su S, Wang Y, Wang J, Xie N, Zhu W, Wen X, Di L, Lu Y, Xu M, Wang M, Chen H, Duo J, Huang Y, Wan D, Tao Z, Zhao S, Chai G, Hao J, Da Y. Peripheral immune profiling highlights a dynamic role of low-density granulocytes in myasthenia gravis. J Autoimmun 2025; 152:103395. [PMID: 40043622 DOI: 10.1016/j.jaut.2025.103395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 02/25/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Myasthenia gravis (MG) is an autoimmune neuromuscular disease marked by dysregulation of several immune cell populations. Here we explored peripheral immune landscape, particularly the role of low-density granulocytes (LDGs). METHODS Single-cell and bulk RNA sequencing analyzed peripheral immune cells from MG patients pre- (n = 4) and after treatment (n = 2), as well as healthy controls (n = 3). Flow cytometry was employed for validating LDG subsets, and various functional assays were conducted to assess their impact on T cell proliferation and differentiation, NET formation, and ROS production. RESULTS Single-cell analysis highlighted a shift towards inflammatory Th1/Th17/Tfh subsets, an intense interferon-mediated immune response, and an expansion of immature myeloid subsets in MG. Flow cytometry showed increased LDGs correlated with disease severity. Unlike myeloid-derived suppressor cells, MG LDGs do not restrict T cell proliferation but induce a pro-inflammatory Th1/Th17 response. They also display enhanced spontaneous neutrophil extracellular traps (NETs) formation and basal reactive oxygen species (ROS) production. LDGs decreased after intravenous immunoglobulin and increased after prolonged immunotherapy in minimal manifestation status (MM), with reduced pro-inflammatory activity. Bulk RNA sequencing revealed significant transcriptional differences in LDGs, especially in cell cycle and granule protein genes. CONCLUSION Peripheral immune profiling sheds light on the intricate role of LDGs in MG. These cells, as a distinct subtype of neutrophils with a proinflammatory phenotype, are notable increased in MG, exacerbating chronic inflammation. Furthermore, immunotherapy expanded LDGs but reduced their proinflammatory capacities. The complex interplay of LDGs in MG underscores their potential as biomarkers and therapeutic targets.
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Affiliation(s)
- Shu Zhang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Qi Wen
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shengyao Su
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yaye Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jingsi Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Nairong Xie
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Wenjia Zhu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Xinmei Wen
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Li Di
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yan Lu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Min Xu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Min Wang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Hai Chen
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jianying Duo
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yue Huang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Dongshan Wan
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Zhen Tao
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Shufang Zhao
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Guoliang Chai
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Junwei Hao
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
| | - Yuwei Da
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
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Bayer AL, Magri Z, Muendlein H, Poltorak A, Alcaide P. MyD88 determines T cell fate through BCAP-PI3K signaling. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2025; 214:vkae037. [PMID: 40073160 PMCID: PMC11952871 DOI: 10.1093/jimmun/vkae037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 11/26/2024] [Indexed: 03/14/2025]
Abstract
The life cycle of effector T cells is determined by signals downstream of the T cell receptor (TCR) that induce activation and proinflammatory activity, or death as part of the process to resolve inflammation. We recently reported that T cell myeloid differentiation primary response 88 (MyD88) tunes down TCR activation and limits T cell survival in the cardiac and tumor inflammatory environments, in contrast to its proinflammatory role in myeloid cells upon toll-like receptor (TLR) recognition of pathogen- and damage-associated molecular patterns. However, the molecular mechanism remains unknown. Here, we report a central regulatory role for MyD88 in T cell apoptosis after TCR activation and Fas ligation through an association with the B cell adaptor for phosphoinositide 3-kinase (B cell activating protein [BCAP]). We show that TCR engagement upregulates MyD88 and BCAP and promotes their interaction, thereby limiting availability of BCAP for downstream TCR-BCAP-PI3K-AKT signaling required for T cell activation and survival, which are enhanced in MyD88-/- activated T cells. Further, MyD88 and BCAP association and localization to the TCR was prevented by lipopolysaccharide (LPS) activation of TLR4 and restored T cell survival in wild-type cells. The enhanced T cell activation markers, proinflammatory signals, and survival advantage observed in MyD88-/- T cells was fully eliminated upon BCAP knockdown in T cells. Our data demonstrate that MyD88 acts downstream of the TCR to regulate T cell fate through its association with BCAP and elucidate a novel molecular mechanism for MyD88 in T cell biology that could be targeted to fine-tune T cell effector function and survival therapeutically.
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Affiliation(s)
- Abraham L Bayer
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University Boston, MA, United States
| | - Zoie Magri
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University Boston, MA, United States
| | - Hayley Muendlein
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University Boston, MA, United States
| | - Alexander Poltorak
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University Boston, MA, United States
| | - Pilar Alcaide
- Department of Immunology, Tufts University School of Medicine, Boston, MA, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University Boston, MA, United States
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Kaushal A. A central role of stimulator of interferon genes' adaptor protein in defensive immune response. Immunol Res 2025; 73:39. [PMID: 39836303 DOI: 10.1007/s12026-024-09587-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 12/27/2024] [Indexed: 01/22/2025]
Abstract
Cytotoxic DNAs, methylation, histones and histones binding proteins are speculated to induce DNA sensors. Under stressed condition, the antigenic patterns, PAMPs and DAMPs, trigger the hyperactive innate response through DNA, DNA-RNA hybrids, oligonucleotides, histones and mtDNA to initiate cGAMP-STING-IFN I cascade. HSV -1&2, HIV, Varicella- Zoster virus, Polyomavirus, Cytomegalovirus, and KSHV negatively regulate the STING-MAVS-TBK-1/1KKE pathway. Implications in STING-PKR-ER regulation often run into causing senescence and organ fibrosis. Post-translational modifications such as, phosphorylation, ubiquitination, SUMOylation, hydrolysis etc. downstream the processing of cGAS-STING that determine the fate of disease prognosis. Self-DNA under normal circumstances is removed through DNase III action; however, its deficiency is the great cause of RA diseases. Regular STING activation in chronic diseases could lead to exacerbate the neurodegenerative disorders due to constant mtDNA leakage. 2' 3' cGAMP or CDN or its associates are being explored as STING agonist therapeutics to treat solid/metastatic tumors to help infiltrate the immune cells, cytokines and chemokines to regulate the protective response. Liposomes, polymer nanoparticles, and cell-derived nanoparticles are also meant to increase the drug efficiency and stability for desired immune response to enhance the IFN I production. This review highlights the implications of cGAMP-STING- IFN I cascade and related pathways involved in the disease prognosis, therapeutics and considering the gaps on different aspects to utilize its greater potential in disease control.
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Yosri M, Dokhan M, Aboagye E, Al Moussawy M, Abdelsamed HA. Mechanisms governing bystander activation of T cells. Front Immunol 2024; 15:1465889. [PMID: 39669576 PMCID: PMC11635090 DOI: 10.3389/fimmu.2024.1465889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/31/2024] [Indexed: 12/14/2024] Open
Abstract
The immune system is endowed with the capacity to distinguish between self and non-self, so-called immune tolerance or "consciousness of the immune system." This type of awareness is designed to achieve host protection by eliminating cells expressing a wide range of non-self antigens including microbial-derived peptides. Such a successful immune response is associated with the secretion of a whole spectrum of soluble mediators, e.g., cytokines and chemokines, which not only contribute to the clearance of infected host cells but also activate T cells that are not specific to the original cognate antigen. This kind of non-specific T-cell activation is called "bystander activation." Although it is well-established that this phenomenon is cytokine-dependent, there is evidence in the literature showing the involvement of peptide/MHC recognition depending on the type of T-cell subset (naive vs. memory). Here, we will summarize our current understanding of the mechanism(s) of bystander T-cell activation as well as its biological significance in a wide range of diseases including microbial infections, cancer, auto- and alloimmunity, and chronic inflammatory diseases such as atherosclerosis.
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Affiliation(s)
- Mohammed Yosri
- The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt
| | - Mohamed Dokhan
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
| | - Elizabeth Aboagye
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
| | - Mouhamad Al Moussawy
- Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Hossam A. Abdelsamed
- Immunology Center of Georgia (IMMCG), Medical College of Georgia (MCG), Augusta University, Augusta, GA, United States
- Department of Physiology, Augusta University, Augusta, GA, United States
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De Salvo C, Osme A, Ghannoum M, Cominelli F, Di Martino L. A New Probiotic Formulation Promotes Resolution of Inflammation in a Crohn's Disease Mouse Model by Inducing Apoptosis in Mucosal Innate Immune Cells. Int J Mol Sci 2024; 25:12066. [PMID: 39596135 PMCID: PMC11593709 DOI: 10.3390/ijms252212066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/02/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
The interaction between gut-residing microorganisms plays a critical role in the pathogenesis of Crohn's disease (CD), where microbiome dysregulation can alter immune responses, leading to unresolved local inflammation. The aim of this study is to analyze the immunomodulatory properties of a recently developed probiotic + amylase blend in the SAMP1/YitFc (SAMP) mouse model of CD-like ileitis. Four groups of SAMP mice were gavaged for 56 days with the following treatments: 1) probiotic strains + amylase (0.25 mg/100 µL PBS); 2) only probiotics; 3) only amylase; PBS-treated controls. Ilea were collected for GeoMx Digital Spatial Profiler (DSP) analysis and histological evaluation. Histology assessment for inflammation indicated a significantly reduced level of ileitis in mice administered the probiotics + amylase blend. DSP analysis showed decreased abundance of neutrophils and increased abundance of dendritic cells, regulatory T cells, and macrophages, with a significant enrichment of five intracellular pathways related to apoptosis, in probiotics + amylase-treated mice. Increased apoptosis occurrence was confirmed by (TdT)- deoxyuridine triphosphate (dUTP)-biotin nick end labeling assay. Our data demonstrate a beneficial role of the probiotic and amylase blend, highlighting an increased apoptosis of innate immunity-associated cell subsets, thus promoting the resolution of inflammation. Hence, we suggest that the developed probiotic enzyme blend may be a therapeutic tool to manage CD and therefore is a candidate formulation to be tested in clinical trials.
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Affiliation(s)
- Carlo De Salvo
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (C.D.S.); (F.C.)
| | - Abdullah Osme
- Department of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Mahmoud Ghannoum
- Center for Medical Mycology and Integrated Microbiome Core, Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Fabio Cominelli
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; (C.D.S.); (F.C.)
- Case Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Luca Di Martino
- Case Digestive Health Research Institute, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
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Shouman S, El-Kholy N, Hussien AE, El-Derby AM, Magdy S, Abou-Shanab AM, Elmehrath AO, Abdelwaly A, Helal M, El-Badri N. SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147. Cell Commun Signal 2024; 22:349. [PMID: 38965547 PMCID: PMC11223399 DOI: 10.1186/s12964-024-01718-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 06/15/2024] [Indexed: 07/06/2024] Open
Abstract
T lymphocytes play a primary role in the adaptive antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, emerging strains posed an immunological challenge, potentially alarming for the next pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine storm elicited by viral infection, which alters the host cell metabolism into a more acidic state. This "hyperlactic acidemia" together with the cytokine storm suppresses T-cell proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may indicate the participation of other receptors or auxiliary proteins on T-cells, that can work alone or in concert with other mechanisms. Therefore, we address the role of CD147-a novel route-for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it also interacts with other co-partners to orchestrate various biological processes. Given these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the discovery of potential therapeutic targets to improve the resilience of our immune system against this rapidly evolving virus.
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Affiliation(s)
- Shaimaa Shouman
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | - Nada El-Kholy
- Department of Drug Discovery, H. Lee Moffit Cancer Center& Research Institute, Tampa, FL, 33612, USA
- Cancer Chemical Biology Ph.D. Program, University of South Florida, Tampa, FL, 33620, USA
| | - Alaa E Hussien
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | - Azza M El-Derby
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | - Shireen Magdy
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | - Ahmed M Abou-Shanab
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | | | - Ahmad Abdelwaly
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
- Institute for Computational Molecular Science, Department of Chemistry, Temple University, Philadelphia, PA, 19122, USA
| | - Mohamed Helal
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
- Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt.
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt.
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Ruggeri Barbaro N, Drashansky T, Tess K, Djedaini M, Hariri R, He S, van der Touw W, Karasiewicz K. Placental circulating T cells: a novel, allogeneic CAR-T cell platform with preserved T-cell stemness, more favorable cytokine profile, and durable efficacy compared to adult PBMC-derived CAR-T. J Immunother Cancer 2024; 12:e008656. [PMID: 38684370 PMCID: PMC11107807 DOI: 10.1136/jitc-2023-008656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2024] [Indexed: 05/02/2024] Open
Abstract
BACKGROUND Chimeric antigen receptor (CAR)-T cell quality and stemness are associated with responsiveness, durability, and memory formation, which benefit clinical responses. Autologous T cell starting material across patients with cancer is variable and CAR-T expansion or potency can fail during manufacture. Thus, strategies to develop allogeneic CAR-T platforms including the identification and expansion of T cell subpopulations that correspond with CAR-T potency are an active area of investigation. Here, we compared CAR-T cells generated from healthy adult peripheral blood T cells versus placental circulating T (P-T) cells. METHODS CAR-T cells from healthy adult peripheral blood mononuclear cells (PBMCs) and P-T cells were generated using the same protocol. CAR-T cells were characterized in detail by a combination of multiparameter flow cytometry, functional assays, and RNA sequencing. In vivo antitumor efficacy and persistence of CAR-T cells were evaluated in a Daudi lymphoma xenograft model. RESULTS P-T cells possess stemness advantages compared with T cells from adult PBMCs. P-T cells are uniformly naïve prior to culture initiation, maintain longer telomeres, resist immune checkpoint upregulation, and resist further differentiation compared with PBMC T cells during CD19 CAR-T manufacture. P-T CD19 CAR-T cells are equally cytotoxic as PBMC-CD19 CAR-T cells but produce less interferon gamma in response to lymphoma. Transcriptome analysis shows P-T CD19 CAR-T cells retain a stem-like gene signature, strongly associate with naïve T cells, an early memory phenotype, and a unique CD4 T cell signature compared with PBMC-CD19 CAR-T cells, which enrich for exhaustion and stimulated memory T cell signatures. Consistent with functional data, P-T CD19 CAR-T cells exhibit attenuated inflammatory cytokine and chemokine gene signatures. In a murine in vivo model, P-T CD19 CAR-T cells eliminate lymphoma beyond 90 days. PBMC-CD19 CAR-T cells provide a non-durable benefit, which only delays disease onset. CONCLUSION We identified characteristics of T cell stemness enriched in P-T CD19 CAR-T which are deficient in PBMC-derived products and translate into response durability in vivo. Our findings demonstrate that placental circulating T cells are a valuable cell source for allogeneic CAR-T products. Stemness advantages inherent to P-T cells translate to in vivo persistence advantages and long-term durable activity.
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Affiliation(s)
| | | | | | | | | | - Shuyang He
- Celularity Inc, Florham Park, New Jersey, USA
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Bayer AL, Smolgovsky S, Ngwenyama N, Hernández-Martínez A, Kaur K, Sulka K, Amrute J, Aronovitz M, Lavine K, Sharma S, Alcaide P. T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation. Circ Res 2023; 133:412-429. [PMID: 37492941 PMCID: PMC10529989 DOI: 10.1161/circresaha.123.323030] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 07/17/2023] [Indexed: 07/27/2023]
Abstract
BACKGROUND Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown. METHODS We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled wild type versus Myd88-/- mouse T cells at the transcript and protein level and performed several functional assays. RESULTS Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated Myd88-/- T cells had increased proinflammatory signaling at the transcript and protein level compared with wild type, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling. CONCLUSIONS Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress.
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Affiliation(s)
| | | | | | | | - Kuljeet Kaur
- Department of Immunology, Tufts University, Boston MA
| | | | - Junedh Amrute
- Department of Medicine, Washington University School of Medicine, Saint Louis MO
| | | | - Kory Lavine
- Department of Medicine, Washington University School of Medicine, Saint Louis MO
| | - Shruti Sharma
- Department of Immunology, Tufts University, Boston MA
| | - Pilar Alcaide
- Department of Immunology, Tufts University, Boston MA
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9
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Hady TF, Hwang B, Waworuntu RL, Ratner BD, Bryers JD. Cells resident to precision templated 40-µm pore scaffolds generate small extracellular vesicles that affect CD4 + T cell phenotypes through regulatory TLR4 signaling. Acta Biomater 2023; 166:119-132. [PMID: 37150279 PMCID: PMC10330460 DOI: 10.1016/j.actbio.2023.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/27/2023] [Accepted: 05/02/2023] [Indexed: 05/09/2023]
Abstract
Precision porous templated scaffolds (PTS) are a hydrogel construct of uniformly sized interconnected spherical pores that induce a pro-healing response (reducing the foreign body reaction, FBR) exclusively when the pores are 30-40µm in diameter. Our previous work demonstrated the necessity of Tregs in the maintenance of PTS pore size specific differences in CD4+ T cell phenotype. Work here characterizes the role of Tregs in the responses to implanted 40µm and 100µm PTS using WT and FoxP3+ cell (Treg) depleted mice. Proteomic analyses indicate that integrin signaling, monocytes/macrophages, cytoskeletal remodeling, inflammatory cues, and vesicule endocytosis may participate in Treg activation and the CD4+ T cell equilibrium modulated by PTS resident cell-derived small extracellular vesicles (sEVs). The role of MyD88-dependent and MyD88-independent TLR4 activation in PTS cell-derived sEV-to-T cell signaling is quantified by treating WT, TLR4ko, and MyD88ko splenic T cells with PTS cell-derived sEVs. STAT3 and mTOR are identified as mechanisms for further study for pore-size dependent PTS cell-derived sEV-to-T cell signaling. STATEMENT OF SIGNIFICANCE: Unique cell populations colonizing only within 40µm pore size PTS generate sEVs that resolve inflammation by modifying CD4+ T cell phenotypes through TLR4 signaling.
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Affiliation(s)
- T F Hady
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA
| | - B Hwang
- Center for Lung Biology, Department of Surgery, University of Washington Seattle, WA 98109, USA
| | - R L Waworuntu
- Center for Lung Biology, Department of Surgery, University of Washington Seattle, WA 98109, USA
| | - B D Ratner
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA
| | - J D Bryers
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA.
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10
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Chen J, Xiang X, Nie L, Guo X, Zhang F, Wen C, Xia Y, Mao L. The emerging role of Th1 cells in atherosclerosis and its implications for therapy. Front Immunol 2023; 13:1079668. [PMID: 36685487 PMCID: PMC9849744 DOI: 10.3389/fimmu.2022.1079668] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/19/2022] [Indexed: 01/07/2023] Open
Abstract
Atherosclerosis is a chronic progressive inflammatory disease of the large and medium-sized artery walls. The molecular mechanisms regulating the onset and progression of atherosclerosis remain unclear. T cells, one of the most common immune cell types in atherosclerotic plaques, are increasingly recognized as a key mediator in the pathogenesis of atherosclerosis. Th1 cells are a subset of CD4+ T helper cells of the adaptive immune system, characterized by the expression of the transcription factor T-bet and secretion of cytokines such as IFN-γ. Converging evidence shows that Th1 cells play a key role in the onset and progression of atherosclerosis. Besides, Th1 is the central mediator to orchestrate the adaptive immune system. In this review, we aim to summarize the complex role of Th1 cells in atherosclerosis and propose novel preventative and therapeutic approaches targeting Th1 cell-associated specific cytokines and receptors to prevent atherogenesis.
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Affiliation(s)
| | | | - Lei Nie
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoqing Guo
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Zhang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Wen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanpeng Xia
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Wen L, Zhang B, Wu X, Liu R, Fan H, Han L, Zhang Z, Ma X, Chu CQ, Shi X. Toll-like receptors 7 and 9 regulate the proliferation and differentiation of B cells in systemic lupus erythematosus. Front Immunol 2023; 14:1093208. [PMID: 36875095 PMCID: PMC9975558 DOI: 10.3389/fimmu.2023.1093208] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 02/02/2023] [Indexed: 02/17/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune illness marked by the loss of immune tolerance and the production of autoantibodies against nucleic acids and other nuclear antigens (Ags). B lymphocytes are important in the immunopathogenesis of SLE. Multiple receptors control abnormal B-cell activation in SLE patients, including intrinsic Toll-like receptors (TLRs), B-cell receptors (BCRs), and cytokine receptors. The role of TLRs, notably TLR7 and TLR9, in the pathophysiology of SLE has been extensively explored in recent years. When endogenous or exogenous nucleic acid ligands are recognized by BCRs and internalized into B cells, they bind TLR7 or TLR9 to activate related signalling pathways and thus govern the proliferation and differentiation of B cells. Surprisingly, TLR7 and TLR9 appear to play opposing roles in SLE B cells, and the interaction between them is still poorly understood. In addition, other cells can enhance TLR signalling in B cells of SLE patients by releasing cytokines that accelerate the differentiation of B cells into plasma cells. Therefore, the delineation of how TLR7 and TLR9 regulate the abnormal activation of B cells in SLE may aid the understanding of the mechanisms of SLE and provide directions for TLR-targeted therapies for SLE.
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Affiliation(s)
- Luyao Wen
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Bei Zhang
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Xinfeng Wu
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Rongzeng Liu
- Department of Immunology, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, China
| | - Hua Fan
- Office of Research & Innovation, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Lei Han
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Zhibo Zhang
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Xin Ma
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Cong-Qiu Chu
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University and VA Portland Health Care System, Portland, OR, United States
| | - Xiaofei Shi
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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12
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Contribution of T- and B-cell intrinsic toll-like receptors to the adaptive immune response in viral infectious diseases. Cell Mol Life Sci 2022; 79:547. [PMID: 36224474 PMCID: PMC9555683 DOI: 10.1007/s00018-022-04582-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/27/2022] [Accepted: 09/30/2022] [Indexed: 11/03/2022]
Abstract
Toll-like receptors (TLRs) comprise a class of highly conserved molecules that recognize pathogen-associated molecular patterns and play a vital role in host defense against multiple viral infectious diseases. Although TLRs are highly expressed on innate immune cells and play indirect roles in regulating antiviral adaptive immune responses, intrinsic expression of TLRs in adaptive immune cells, including T cells and B cells, cannot be ignored. TLRs expressed in CD4 + and CD8 + T cells play roles in enhancing TCR signal-induced T-cell activation, proliferation, function, and survival, serving as costimulatory molecules. Gene knockout of TLR signaling molecules has been shown to diminish antiviral adaptive immune responses and affect viral clearance in multiple viral infectious animal models. These results have highlighted the critical role of TLRs in the long-term immunological control of viral infection. This review summarizes the expression and function of TLR signaling pathways in T and B cells, focusing on the in vitro and vivo mechanisms and effects of intrinsic TLR signaling in regulating T- and B-cell responses during viral infection. The potential clinical use of TLR-based immune regulatory drugs for viral infectious diseases is also explored.
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13
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Yu T, Yu SK, Xiang Y, Lu KH, Sun M. Revolution of CAR Engineering For Next-Generation Immunotherapy In Solid Tumors. Front Immunol 2022; 13:936496. [PMID: 35903099 PMCID: PMC9315443 DOI: 10.3389/fimmu.2022.936496] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/16/2022] [Indexed: 01/01/2023] Open
Abstract
Chimeric antigen receptor (CAR)-T cells have enormous potentials for clinical therapies. The CAR-T therapy has been approved for treating hematological malignancies. However, their application is limited in solid tumors owing to antigen loss and mutation, physical barriers, and an immunosuppressive tumor microenvironment. To overcome the challenges of CAR-T, increasing efforts are put into developing CAR-T to expand its applied ranges. Varied receptors are utilized for recognizing tumor-associated antigens and relieving immunosuppression. Emerging co-stimulatory signaling is employed for CAR-T activation. Furthermore, other immune cells such as NK cells and macrophages have manifested potential for delivering CAR. Hence, we collected and summarized the last advancements of CAR engineering from three aspects, namely, the ectodomains, endogenous domains, and immune cells, aiming to inspire the design of next-generation adoptive immunotherapy for treating solid tumors.
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Affiliation(s)
- Tao Yu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shao-kun Yu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Xiang
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kai-Hua Lu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- *Correspondence: Kai-Hua Lu, ; Ming Sun,
| | - Ming Sun
- Suzhou Cancer Center Core Laboratory, Suzhou Municipal Hospital, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
- *Correspondence: Kai-Hua Lu, ; Ming Sun,
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14
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Colciaghi F, Costanza M. Unveiling Leukocyte Extracellular Traps in Inflammatory Responses of the Central Nervous System. Front Immunol 2022; 13:915392. [PMID: 35844591 PMCID: PMC9283689 DOI: 10.3389/fimmu.2022.915392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/07/2022] [Indexed: 11/13/2022] Open
Abstract
Over the past nearly two decades, increasing evidence has uncovered how immune cells can actively extrude genetic material to entrap invading pathogens or convey sterile inflammatory signals that contribute to shaping immune responses. Originally identified in neutrophils, the release of decondensed chromatin fibers decorated with antimicrobial proteins, called extracellular traps (ETs), has been recognized as a specific form of programmed inflammatory cell death, which is now known to occur in several other leukocytes. Subsequent reports have shown that self-DNA can be extruded from immune cells even in the absence of cell death phenomena. More recent data suggest that ETs formation could exacerbate neuroinflammation in several disorders of the central nervous system (CNS). This review article provides an overview of the varied types, sources, and potential functions of extracellular DNA released by immune cells. Key evidence suggesting the involvement of ETs in neurodegenerative, traumatic, autoimmune, and oncological disorders of the CNS will be discussed, outlining ongoing challenges and drawing potentially novel lines of investigation.
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Affiliation(s)
- Francesca Colciaghi
- Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - Massimo Costanza
- Molecular Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
- *Correspondence: Massimo Costanza,
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15
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Targeting toll-like receptors on T cells as a therapeutic strategy against tumors. Int Immunopharmacol 2022; 107:108708. [DOI: 10.1016/j.intimp.2022.108708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/05/2022] [Accepted: 03/13/2022] [Indexed: 12/11/2022]
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16
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Akesolo O, Buey B, Beltrán-Visiedo M, Giraldos D, Marzo I, Latorre E. Toll-like receptors: new targets for multiple myeloma treatment? Biochem Pharmacol 2022; 199:114992. [DOI: 10.1016/j.bcp.2022.114992] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 02/08/2023]
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17
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Thomas S, Ouhtit A, Al Khatib HA, Eid AH, Mathew S, Nasrallah GK, Emara MM, Al Maslamani MA, Yassine HM. Burden and Disease Pathogenesis of Influenza and Other Respiratory Viruses in Diabetic Patients. J Infect Public Health 2022; 15:412-424. [DOI: 10.1016/j.jiph.2022.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/24/2022] [Accepted: 03/07/2022] [Indexed: 02/07/2023] Open
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18
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Jiao A, Sun C, Wang X, Lei L, Liu H, Li W, Yang X, Zheng H, Ding R, Zhu K, Su Y, Zhang C, Zhang L, Zhang B. DExD/H-box helicase 9 intrinsically controls CD8 + T cell-mediated antiviral response through noncanonical mechanisms. SCIENCE ADVANCES 2022; 8:eabk2691. [PMID: 35138904 PMCID: PMC8827654 DOI: 10.1126/sciadv.abk2691] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Upon virus infection, CD8+ T cell accumulation is tightly controlled by simultaneous proliferation and apoptosis. However, it remains unclear how TCR signal coordinates these events to achieve expansion and effector cell differentiation. We found that T cell-specific deletion of nuclear helicase Dhx9 led to impaired CD8+ T cell survival, effector differentiation, and viral clearance. Mechanistically, Dhx9 acts as the key regulator to ensure LCK- and CD3ε-mediated ZAP70 phosphorylation and ERK activation to protect CD8+ T cells from apoptosis before proliferative burst. Dhx9 directly regulates Id2 transcription to control effector CD8+ T cell differentiation. The DSRM and OB_Fold domains are required for LCK binding and Id2 transcription, respectively. Dhx9 expression is predominantly increased in effector CD8+ T cells of COVID-19 patients. Therefore, we revealed a previously unknown regulatory mechanism that Dhx9 protects activated CD8+ T cells from apoptosis and ensures effector differentiation to promote antiviral immunity independent of nuclear sensor function.
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Affiliation(s)
- Anjun Jiao
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China
| | - Chenming Sun
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China
| | - Xin Wang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China
| | - Lei Lei
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China
| | - Haiyan Liu
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Wenhui Li
- Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- Suzhou Institute of Systems Medicine, Suzhou 215123, China
| | - Xiaofeng Yang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China
| | - Huiqiang Zheng
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Renyi Ding
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Kun Zhu
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Yanhong Su
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Cangang Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
| | - Lianjun Zhang
- Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
- Suzhou Institute of Systems Medicine, Suzhou 215123, China
- Corresponding author. (B.Z.); (L.Z.)
| | - Baojun Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China
- Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, China
- Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China
- Corresponding author. (B.Z.); (L.Z.)
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19
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Abd-Elhakim YM, Omran BHF, Ezzeldein SA, Ahmed AI, El-Sharkawy NI, Mohamed AAR. Time-dependent expression of high-mobility group box-1 and toll-like receptors proteins as potential determinants of skin wound age in rats: Forensic implication. Int J Legal Med 2022; 136:1781-1789. [PMID: 35132471 PMCID: PMC9576669 DOI: 10.1007/s00414-022-02788-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 01/21/2022] [Indexed: 12/03/2022]
Abstract
The skin wound age determination in living subjects is an imperative task for forensic experts. In this study, we investigated the time-dependent expression of high-mobility group box-1 (HMGB1) and toll-like receptors 2 and 4 (TLR2 and 4) in rat skin wounds using real-time PCR and seek their forensic potentials during the skin wound repair process. In addition, the levels of serum pro-inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6)), as well as nitric oxide (NO) production, were measured. The wound tissue and serum samples were collected after 30 min, 2 h, 6 h, 12 h, 1 day, 3 days, 5 days, and 7 days after incision. As a control (zero time), skin specimens and blood samples were collected without incision. The results reveal that the HMGB1, TLR2, and TLR4 expression levels were increased in a time-dependent manner until the first day where the peak level was achieved for the three tested genes compared with the zero time. On the 7th day, the statistical significance was lost for TLR2 and TLR4 but persisted for HMGB1. The serum TNF-α, IL6, and NO levels peaked within 30 min and 1st and 3rd day after injury, respectively. On the 7th day after incision, no significant differences exist in the TNF-α serum level compared to the control group, but the statistical significance persisted for IL6 and NO. It was apparent that the analyzed genes in the wound tissues showed higher R2 values rather than the serum biochemical indicators. Of note, a strong positive correlation was evident between the HMGB1 and that of TLR2 and TLR4 relative expression as well as IL-6 serum level. Conclusively, based on the observed changes in the analyzed markers in wound tissues and serum and R2 values obtained from mathematical models established to determine the wound age, the relative expression of HMGB1, TLR2, and TLR4 could be a reliable indicator for wound age determination in living subjects. Further investigation of these markers and mathematical models in human tissues is necessary.
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Affiliation(s)
- Yasmina M Abd-Elhakim
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
| | - Bothina H F Omran
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt
| | - Shimaa A Ezzeldein
- Department of Surgery, Anesthesiology and Radiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Amany I Ahmed
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Nabela I El-Sharkawy
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Amany Abdel-Rahman Mohamed
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
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20
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Benoit-Lizon I, Jacquin E, Rivera Vargas T, Richard C, Roussey A, Dal Zuffo L, Martin T, Melis A, Vinokurova D, Shahoei SH, Baeza Garcia A, Pignol C, Giorgiutti S, Carapito R, Boidot R, Végran F, Flavell RA, Ryffel B, Nelson ER, Soulas-Sprauel P, Lawrence T, Apetoh L. CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells. J Immunother Cancer 2022; 10:jitc-2021-003459. [PMID: 35091453 PMCID: PMC8804688 DOI: 10.1136/jitc-2021-003459] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2021] [Indexed: 12/20/2022] Open
Abstract
Background While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive. Methods Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances TH9 cell antitumor activity against mouse melanoma upon adoptive transfer. Results We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of TH1 and TH9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of TH1 cell differentiation. However, STING activation favors TH9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on TH1 and TH9-derived cytokines, and STING activation enhances the antitumor activity of TH9 cells upon adoptive transfer. Conclusion Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.
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Affiliation(s)
- Isis Benoit-Lizon
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Elise Jacquin
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
- INSERM, UMR-S 1193, Université Paris-Saclay, Châtenay-Malabry, France
| | - Thaiz Rivera Vargas
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Corentin Richard
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Aurélie Roussey
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Ludivine Dal Zuffo
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Tiffany Martin
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Andréa Melis
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Daria Vinokurova
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Sayyed Hamed Shahoei
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Alvaro Baeza Garcia
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Cassandre Pignol
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
| | - Stéphane Giorgiutti
- INSERM UMR - S1109, Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - Raphaël Carapito
- Laboratoire d'ImmunoRhumatologie Moléculaire, GENOMAX platform, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Strasbourg, France
| | - Romain Boidot
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
- Department of Biology and Pathology of Tumors, Centre Georges François Leclerc, Dijon, France
| | - Frédérique Végran
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
- Department of Biology and Pathology of Tumors, Centre Georges François Leclerc, Dijon, France
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, New Heaven, CT, USA
| | - Bernhard Ryffel
- UMR 7355, Experimental and Molecular Immunology and Neurogenetics, CNRS, Orléans, France
- Department of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Eric R Nelson
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Cancer Center at Illinois, Urbana Champaign, Illinois, USA
- University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Pauline Soulas-Sprauel
- INSERM UMR-S1109, Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Faculty of Pharmacy, Université de Strasbourg, Strasbourg, France
| | - Toby Lawrence
- Centre d'Immunologie de Marseille-Luminy, Université Aix-Marseille, INSERM, CNRS, Marseille, France
| | - Lionel Apetoh
- INSERM, U1231, Dijon, France
- UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France
- INSERM, U1100, Tours, France
- Faculté de Médecine, Université de Tours, Tours, France
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21
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Wilson AS, Randall KL, Pettitt JA, Ellyard JI, Blumenthal A, Enders A, Quah BJ, Bopp T, Parish CR, Brüstle A. Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2. Nat Commun 2022; 13:528. [PMID: 35082281 PMCID: PMC8792063 DOI: 10.1038/s41467-022-28172-4] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 01/08/2022] [Indexed: 01/08/2023] Open
Abstract
Neutrophils perform critical functions in the innate response to infection, including through the production of neutrophil extracellular traps (NETs) - web-like DNA structures which are extruded from neutrophils upon activation. Elevated levels of NETs have been linked to autoimmunity but this association is poorly understood. By contrast, IL-17 producing Th17 cells are a key player in various autoimmune diseases but are also crucial for immunity against fungal and bacterial infections. Here we show that NETs, through their protein component histones, directly activate T cells and specifically enhance Th17 cell differentiation. This modulatory role of neutrophils, NETs and their histones is mediated downstream of TLR2 in T cells, resulting in phosphorylation of STAT3. The innate stimulation of a specific adaptive immune cell subset provides an additional mechanism demonstrating a direct link between neutrophils, NETs and T cell autoimmunity.
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Affiliation(s)
- Alicia S Wilson
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Katrina L Randall
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.,ANU Medical School, The Australian National University, Canberra, ACT, Australia
| | - Jessica A Pettitt
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Julia I Ellyard
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Antje Blumenthal
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Anselm Enders
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Benjamin J Quah
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Tobias Bopp
- Institute for Immunology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Christopher R Parish
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | - Anne Brüstle
- The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
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22
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Significance of bystander T cell activation in microbial infection. Nat Immunol 2022; 23:13-22. [PMID: 34354279 DOI: 10.1038/s41590-021-00985-3] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023]
Abstract
During microbial infection, pre-existing memory CD8+ T cells that are not specific for the infecting pathogens can be activated by cytokines without cognate antigens, termed bystander activation. Studies in mouse models and human patients demonstrate bystander activation of memory CD8+ T cells, which exerts either protective or detrimental effects on the host, depending on the infection model or disease. Research has elucidated mechanisms underlying the bystander activation of CD8+ T cells in terms of the responsible cytokines and the effector mechanisms of bystander-activated CD8+ T cells. In this Review, we describe the history of research on bystander CD8+ T cell activation as well as evidence of bystander activation. We also discuss the mechanisms and immunopathological roles of bystander activation in various microbial infections.
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23
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Wu Y, Wang M, Yin H, Ming S, Li X, Jiang G, Liu Y, Wang P, Zhou G, Liu L, Gong S, Zhou H, Shan H, Huang X. TREM-2 is a sensor and activator of T cell response in SARS-CoV-2 infection. SCIENCE ADVANCES 2021; 7:eabi6802. [PMID: 34878838 PMCID: PMC8654301 DOI: 10.1126/sciadv.abi6802] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Limited understanding of T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impeded vaccine development and drug discovery for coronavirus disease 2019 (COVID-19). We found that triggering receptor expressed on myeloid cells 2 (TREM-2) was induced in T cells in the blood and lungs of patients with COVID-19. After binding to SARS-CoV-2 membrane (M) protein through its immunoglobulin domain, TREM-2 then activated the CD3ζ/ZAP70 complex, leading to STAT1 phosphorylation and T-bet transcription. In vitro stimulation with M protein-reconstituted pseudovirus or recombinant M protein, and TREM-2 promoted the T helper cell 1 (TH1) cytokines interferon-γ and tumor necrosis factor. In vivo infection of CD4–TREM-2 conditional knockout mice with murine coronavirus mouse hepatitis virus A-59 showed that intrinsic TREM-2 in T cells enhanced TH1 response and viral clearance, thus aggravating lung destruction. These findings demonstrate a previously unidentified role for TREM-2 in SARS-CoV-2 infection, and suggest potential strategies for drug discovery and clinical management of COVID-19.
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Affiliation(s)
- Yongjian Wu
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province 519000, China
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong Province 510623, China
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong Province 511518, China
| | - Manni Wang
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Huan Yin
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Siqi Ming
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China
| | - Xingyu Li
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Guanmin Jiang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Ye Liu
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Peihui Wang
- Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, China
| | - Guangde Zhou
- National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China
| | - Lei Liu
- National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong Province 510623, China
| | - Haibo Zhou
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong Province 511518, China
| | - Hong Shan
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province 519000, China
| | - Xi Huang
- Center for Infection and Immunity, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
- Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province 519000, China
- Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong Province 510623, China
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan, Guangdong Province 511518, China
- National Clinical Research Center for Infectious Disease, Shenzhen Third People’s Hospital, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong Province 518112, China
- Corresponding author.
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24
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Bayer AL, Alcaide P. MyD88: At the heart of inflammatory signaling and cardiovascular disease. J Mol Cell Cardiol 2021; 161:75-85. [PMID: 34371036 PMCID: PMC8629847 DOI: 10.1016/j.yjmcc.2021.08.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/27/2021] [Accepted: 08/02/2021] [Indexed: 12/20/2022]
Abstract
Cardiovascular disease is a leading cause of death worldwide and is associated with systemic inflammation. In depth study of the cell-specific signaling mechanisms mediating the inflammatory response is vital to improving anti-inflammatory therapies that reduce mortality and morbidity. Cellular damage in the cardiovascular system results in the release of damage associated molecular patterns (DAMPs), also known as "alarmins," which activate myeloid cells through the adaptor protein myeloid differentiation primary response 88 (MyD88). MyD88 is broadly expressed in most cell types of the immune and cardiovascular systems, and its role often differs in a cardiovascular disease context and cell specific manner. Herein we review what is known about MyD88 in the setting of a variety of cardiovascular diseases, discussing cell specific functions and the relative contributions of MyD88-dependent vs. independent alarmin triggered inflammatory signaling. The widespread involvement of these pathways in cardiovascular disease, and their largely unexplored complexity, sets the stage for future in depth mechanistic studies that may place MyD88 in both immune and non-immune cell types as an attractive target for therapeutic intervention in cardiovascular disease.
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Affiliation(s)
- Abraham L Bayer
- Department of Immunology, Tufts University School of Medicine. 136 Harrison Ave, Boston, MA 02111, United States of America.
| | - Pilar Alcaide
- Department of Immunology, Tufts University School of Medicine. 136 Harrison Ave, Boston, MA 02111, United States of America.
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25
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Tanno H, Kanno E, Kurosaka S, Oikawa Y, Watanabe T, Sato K, Kasamatsu J, Miyasaka T, Ishi S, Shoji M, Takagi N, Imai Y, Ishii K, Tachi M, Kawakami K. Topical Administration of Heat-Killed Enterococcus faecalis Strain KH2 Promotes Re-Epithelialization and Granulation Tissue Formation during Skin Wound-Healing. Biomedicines 2021; 9:1520. [PMID: 34829749 PMCID: PMC8614852 DOI: 10.3390/biomedicines9111520] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/14/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022] Open
Abstract
Lactic acid bacteria (LAB) are known to have beneficial effects on immune responses when they are orally administered as bacterial products. Although the beneficial effects of LAB have been reported for the genera Lactobacillus and Lactococcus, little has been uncovered on the effects of the genus Enterococcus on skin wound-healing. In this study, we aimed to clarify the effect of heat-killed Enterococcus faecalis KH2 (heat-killed KH2) strain on the wound-healing process and to evaluate the therapeutic potential in chronic skin wounds. We analyzed percent wound closure, re-epithelialization, and granulation area, and cytokine and growth factor production. We found that heat-killed KH2 contributed to the acceleration of re-epithelialization and the formation of granulation tissue by inducing tumor necrosis factor-α, interleukin-6, basic fibroblast growth factor, transforming growth factor (TGF)-β1, and vascular endothelial growth factor production. In addition, heat-killed KH2 also improved wound closure, which was accompanied by the increased production of TGF-β1 in diabetic mice. Topical administration of heat-killed KH2 might have therapeutic potential for the treatment of chronic skin wounds in diabetes mellitus. In the present study, we concluded that heat-killed KH2 promoted skin wound-healing through the formation of granulation tissues and the production of inflammatory cytokines and growth factors.
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Affiliation(s)
- Hiromasa Tanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan;
| | - Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan;
| | - Shiho Kurosaka
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (N.T.); (Y.I.); (M.T.)
| | - Yukari Oikawa
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (Y.O.); (K.S.); (K.I.); (K.K.)
| | - Takumi Watanabe
- Bio-Lab Co., Ltd., 2-1-3 Komagawa, Hidaka-shi 350-1249, Japan;
| | - Ko Sato
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (Y.O.); (K.S.); (K.I.); (K.K.)
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan;
| | - Jun Kasamatsu
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan;
| | - Tomomitsu Miyasaka
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan;
| | - Shinyo Ishi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (N.T.); (Y.I.); (M.T.)
| | - Miki Shoji
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (N.T.); (Y.I.); (M.T.)
| | - Naoyuki Takagi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (N.T.); (Y.I.); (M.T.)
| | - Yoshimichi Imai
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (N.T.); (Y.I.); (M.T.)
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (Y.O.); (K.S.); (K.I.); (K.K.)
| | - Masahiro Tachi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (N.T.); (Y.I.); (M.T.)
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (Y.O.); (K.S.); (K.I.); (K.K.)
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan;
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26
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Wu Y, Wu M, Ming S, Zhan X, Hu S, Li X, Yin H, Cao C, Liu J, Li J, Wu Z, Zhou J, Liu L, Gong S, He D, Huang X. TREM-2 promotes Th1 responses by interacting with the CD3ζ-ZAP70 complex following Mycobacterium tuberculosis infection. J Clin Invest 2021; 131:137407. [PMID: 34623322 DOI: 10.1172/jci137407] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 07/20/2021] [Indexed: 12/16/2022] Open
Abstract
Triggering receptor expressed on myeloid cells 2 (TREM-2) is a modulator of pattern recognition receptors on innate immune cells that regulates the inflammatory response. However, the role of TREM-2 in in vivo models of infection and inflammation remains controversial. Here, we demonstrated that TREM-2 expression on CD4+ T cells was induced by Mycobacterium tuberculosis infection in both humans and mice and positively associated with T cell activation and an effector memory phenotype. Activation of TREM-2 in CD4+ T cells was dependent on interaction with the putative TREM-2 ligand expressed on DCs. Unlike the observation in myeloid cells that TREM-2 signals through DAP12, in CD4+ T cells, TREM-2 interacted with the CD3ζ-ZAP70 complex as well as with the IFN-γ receptor, leading to STAT1/-4 activation and T-bet transcription. In addition, an infection model using reconstituted Rag2-/- mice (with TREM-2-KO vs. WT cells or TREM-2+ vs. TREM-2-CD4+ T cells) or CD4+ T cell-specific TREM-2 conditional KO mice demonstrated that TREM-2 promoted a Th1-mediated host defense against M. tuberculosis infection. Taken together, these findings reveal a critical role of TREM-2 in evoking proinflammatory Th1 responses that may provide potential therapeutic targets for infectious and inflammatory diseases.
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Affiliation(s)
- Yongjian Wu
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.,Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province, China.,Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Minhao Wu
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Siqi Ming
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.,National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of the Southern University of Science and Technology, Shenzhen, Guangdong Province, China
| | - Xiaoxia Zhan
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Shengfeng Hu
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Xingyu Li
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Huan Yin
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Can Cao
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Jiao Liu
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Jinai Li
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Zhilong Wu
- The Fourth People's Hospital of Foshan, Foshan, China
| | - Jie Zhou
- The Fourth People's Hospital of Foshan, Foshan, China
| | - Lei Liu
- National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of the Southern University of Science and Technology, Shenzhen, Guangdong Province, China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Duanman He
- Shantou No. 3 People's Hospital, Shantou, Guangdong Province, China
| | - Xi Huang
- Center for Infection and Immunity, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong Provincial Key Laboratory of Biomedical Imaging, and Department of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.,Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong Province, China.,Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong Province, China.,National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of the Southern University of Science and Technology, Shenzhen, Guangdong Province, China
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27
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Jin Y, Zhuang Y, Dong X, Liu M. Development of CpG oligodeoxynucleotide TLR9 agonists in anti-cancer therapy. Expert Rev Anticancer Ther 2021; 21:841-851. [PMID: 33831324 DOI: 10.1080/14737140.2021.1915136] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
INTRODUCTION Toll-like receptor-9(TLR9) can recognize the foreign unmethylated CpG DNA, and thus intrigue a strong Th1 response which plays a crucial role in the innate and adaptive immune responses. To date, CpG oligodeoxynucleotide (ODN)-based TLR9 agonists have undergone four generations. Each generations' breakthroughs in immune activation, safety profiles and pharmacokinetic properties were confirmed by both preclinical and clinical studies. AREAS COVERED We reviewed the development and major clinical trials of TLR9 agonists and summarized the optimization strategies of each generation. The applications, limitations and prospects of TLR9 agonists in cancer immunotherapy are also discussed. EXPERT OPINION Clinical trials of CpG ODN TLR9 agonists as a single agent demonstrated insufficient efficacy to reverse the immunosuppressive status of majority of patients with high tumor burden. Therefore, more efforts are now been carried out in combination with chemotherapy, radiotherapy and immunotherapy maintenance therapy as well as vaccine adjuvant. Importantly, the synergistic and complementary effect of TLR9 agonists and tumor immune checkpoint inhibitor therapy is expected to exert greater potential. On the other hand, the double-edged sword effect of TLR9 activation in tumor and toxic effect reported in combination therapies should be noted and further studies required.
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Affiliation(s)
- Yizhen Jin
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China
| | - Yuxin Zhuang
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P.R. China.,Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, P.R. China
| | - Mei Liu
- Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, P.R. China
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28
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Kologrivova I, Shtatolkina M, Suslova T, Ryabov V. Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of Inflammation and Repair After Myocardial Infarction. Front Immunol 2021; 12:664457. [PMID: 33868315 PMCID: PMC8050340 DOI: 10.3389/fimmu.2021.664457] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/16/2021] [Indexed: 12/13/2022] Open
Abstract
The burden of heart failure (HF), developing after myocardial infarction MI, still represents a major issue in clinical practice. Failure of appropriate resolution of inflammation during post-myocardial injury is associated with unsuccessful left ventricular remodeling and underlies HF pathogenesis. Cells of the immune system have been shown to mediate both protective and damaging effects in heart remodeling. This ambiguity of the role of the immune system and inconsistent results of the recent clinical trials question the benefits of anti-inflammatory therapies during acute MI. The present review will summarize knowledge of the roles that different cells of the immune system play in the process of post-infarct cardiac healing. Data on the phenotype, active molecules and functions of the immune cells, based on the results of both experimental and clinical studies, will be provided. For some cellular subsets, such as macrophages, neutrophils, dendritic cells and lymphocytes, an anti-inflammatory activity has been attributed to the specific subpopulations. Activity of other cells, such as eosinophils, mast cells, natural killer (NK) cells and NKT cells has been shown to be highly dependent of the signals created by micro-environment. Also, new approaches for classification of cellular phenotypes based on the single-cell RNA sequencing allow better understanding of the phenotype of the cells involved in resolution of inflammation. Possible perspectives of immune-mediated therapy for AMI patients are discussed in the conclusion. We also outline unresolved questions that need to be solved in order to implement the current knowledge on the role of the immune cells in post-MI tissue repair into practice.
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Affiliation(s)
- Irina Kologrivova
- Department of Clinical Laboratory Diagnostics, Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia
| | - Marina Shtatolkina
- Department of Emergency Cardiology, Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia
| | - Tatiana Suslova
- Department of Clinical Laboratory Diagnostics, Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia
| | - Vyacheslav Ryabov
- Department of Emergency Cardiology, Cardiology Research Institute, Tomsk National Research Medical Centre, Russian Academy of Sciences, Tomsk, Russia.,Division of Cardiology, Department of Professional Development and Retraining, Siberian State Medical University, Tomsk, Russia
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Sponaas AM, Waage A, Vandsemb EN, Misund K, Børset M, Sundan A, Slørdahl TS, Standal T. Bystander Memory T Cells and IMiD/Checkpoint Therapy in Multiple Myeloma: A Dangerous Tango? Front Immunol 2021; 12:636375. [PMID: 33679794 PMCID: PMC7928324 DOI: 10.3389/fimmu.2021.636375] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/26/2021] [Indexed: 12/19/2022] Open
Abstract
In this review article we discuss the role of the memory T cells in multiple myeloma (MM) and how they may influence immune responses in patients that received immunomodulating drugs and check point therapy.
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Affiliation(s)
- Anne Marit Sponaas
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Anders Waage
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Hematology, St.Olavs Hospital, Trondheim, Norway
| | - Esten N Vandsemb
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Kristine Misund
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Magne Børset
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Immunology and Transfusion Medicine, St.Olavs Hospital, Trondheim, Norway
| | - Anders Sundan
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Tobias Schmidt Slørdahl
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Hematology, St.Olavs Hospital, Trondheim, Norway
| | - Therese Standal
- Department of Clinical and Molecular Medicine, Center for Myeloma Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Clinical and Molecular Medicine, Center of Molecular Inflammation Research, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
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30
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Aksel EG, Akyüz B. Effect of LPS and LTA stimulation on the expression of TLR-pathway genes in PBMCs of Akkaraman lambs in vivo. Trop Anim Health Prod 2021; 53:65. [PMID: 33392825 PMCID: PMC7779097 DOI: 10.1007/s11250-020-02491-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 12/02/2020] [Indexed: 01/30/2023]
Abstract
This is the first study investigating the changes in some gene expressions related to the TLR pathway in vivo in sheep. Lipopolysaccharide (LPS) and lipoteichoic acid (LTA) molecules were administrated separately and in combination to the Akkaraman lambs via intranasal route. For this purpose, 28 lambs were distributed into four groups (LPS, LTA, LPS + LTA, and control, n = 7). Blood samples were collected to isolate the peripheral blood mononuclear cells (PBMCs) at 24 h and on day 7. Expression levels of TLR2, TLR4, MyD88, TRAF6, TNF-α, IL-1ß, IL-6, IL-10, NF-κß, and IFN-γ genes were determined by qRT-PCR. Increases were determined in the expression data of TLR2 [LPS (P < 0.05) and LTA + LPS (P < 0.01)], TLR4 [LTA + LPS (P < 0.05)], TNF-α, IL-10 [LTA + LPS (P < 0.05)], and IFN-γ genes in all groups in the mRNA expression analysis of PBMCs isolated at 24 h whereas decreases were determined in the expression levels of these genes on day 7. The combination of LPS + LTA stimulated lamb PBMCs more effectively than separate administration of LPS and LTA at 24 h. Therefore, this article may contribute to the understanding the host-pathogen interaction of respiratory-transmitted bacterial diseases concerning PBMCs at 24 h and on day 7. Also this study may contribute to the dose adjustment for bacterial vaccine studies in sheep. Experimental application doses will be helpful for in vivo and in vitro drug and vaccine development studies in the fields of pharmacology and microbiology.
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Affiliation(s)
- Esma Gamze Aksel
- Department of Genetic, Faculty of Veterinary Medicine, Erciyes University, 38039, Kayseri, Turkey.
| | - Bilal Akyüz
- Department of Genetic, Faculty of Veterinary Medicine, Erciyes University, 38039, Kayseri, Turkey
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31
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Suárez LJ, Garzón H, Arboleda S, Rodríguez A. Oral Dysbiosis and Autoimmunity: From Local Periodontal Responses to an Imbalanced Systemic Immunity. A Review. Front Immunol 2020; 11:591255. [PMID: 33363538 PMCID: PMC7754713 DOI: 10.3389/fimmu.2020.591255] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/09/2020] [Indexed: 12/15/2022] Open
Abstract
The current paradigm of onset and progression of periodontitis includes oral dysbiosis directed by inflammophilic bacteria, leading to altered resolution of inflammation and lack of regulation of the inflammatory responses. In the construction of explanatory models of the etiopathogenesis of periodontal disease, autoimmune mechanisms were among the first to be explored and historically, for more than five decades, they have been described in an isolated manner as part of the tissue damage process observed in periodontitis, however direct participation of these mechanisms in the tissue damage is still controversial. Autoimmunity is affected by genetic and environmental factors, leading to an imbalance between the effector and regulatory responses, mostly associated with failed resolution mechanisms. However, dysbiosis/infection and chronic inflammation could trigger autoimmunity by several mechanisms including bystander activation, dysregulation of toll-like receptors, amplification of autoimmunity by cytokines, epitope spreading, autoantigens complementarity, autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, and activation or inhibition of receptors related to autoimmunity by microorganisms. Even though autoreactivity in periodontitis is biologically plausible, the associated mechanisms could be related to non-pathologic responses which could even explain non-recognized physiological functions. In this review we shall discuss from a descriptive point of view, the autoimmune mechanisms related to periodontitis physio-pathogenesis and the participation of oral dysbiosis on local periodontal autoimmune responses as well as on different systemic inflammatory diseases.
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Affiliation(s)
- Lina J. Suárez
- Departamento de Ciencias Básicas y Medicina Oral, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Hernan Garzón
- Grupo de Investigación en Salud Oral, Universidad Antonio Nariño, Bogotá, Colombia
| | - Silie Arboleda
- Unidad de Investigación en Epidemiologia Clínica Oral (UNIECLO), Universidad El Bosque, Bogotá, Colombia
| | - Adriana Rodríguez
- Centro de Investigaciones Odontológicas, Pontificia Universidad Javeriana, Bogotá, Colombia
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32
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Checa J, Aran JM. Airway Redox Homeostasis and Inflammation Gone Awry: From Molecular Pathogenesis to Emerging Therapeutics in Respiratory Pathology. Int J Mol Sci 2020; 21:E9317. [PMID: 33297418 PMCID: PMC7731288 DOI: 10.3390/ijms21239317] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 12/05/2020] [Indexed: 02/06/2023] Open
Abstract
As aerobic organisms, we are continuously and throughout our lifetime subjected to an oxidizing atmosphere and, most often, to environmental threats. The lung is the internal organ most highly exposed to this milieu. Therefore, it has evolved to confront both oxidative stress induced by reactive oxygen species (ROS) and a variety of pollutants, pathogens, and allergens that promote inflammation and can harm the airways to different degrees. Indeed, an excess of ROS, generated intrinsically or from external sources, can imprint direct damage to key structural cell components (nucleic acids, sugars, lipids, and proteins) and indirectly perturb ROS-mediated signaling in lung epithelia, impairing its homeostasis. These early events complemented with efficient recognition of pathogen- or damage-associated recognition patterns by the airway resident cells alert the immune system, which mounts an inflammatory response to remove the hazards, including collateral dead cells and cellular debris, in an attempt to return to homeostatic conditions. Thus, any major or chronic dysregulation of the redox balance, the air-liquid interface, or defects in epithelial proteins impairing mucociliary clearance or other defense systems may lead to airway damage. Here, we review our understanding of the key role of oxidative stress and inflammation in respiratory pathology, and extensively report current and future trends in antioxidant and anti-inflammatory treatments focusing on the following major acute and chronic lung diseases: acute lung injury/respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and cystic fibrosis.
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Affiliation(s)
| | - Josep M. Aran
- Immune-Inflammatory Processes and Gene Therapeutics Group, IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, Spain;
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33
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Yin B, Liu H, Tan B, Dong X, Chi S, Yang Q, Zhang S. Preliminary study of mechanisms of intestinal inflammation induced by plant proteins in juvenile hybrid groupers (♀Epinephelus fuscoguttatus×♂E. lanceolatu). FISH & SHELLFISH IMMUNOLOGY 2020; 106:341-356. [PMID: 32739533 DOI: 10.1016/j.fsi.2020.07.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/29/2020] [Accepted: 07/14/2020] [Indexed: 06/11/2023]
Abstract
Fish fed a high plant protein diet exhibit intestinal inflammation, the mechanism of which needs to be clarified. We preliminarily elucidate the mechanism of the TLRs/MyD88-PI3K/Akt signalling pathway in intestinal inflammation induced by plant proteins. The diets contained 60% fish meal (FM, controls), or had 45% of the fish meal protein replaced by soybean meal (SBM), peanut meal (PM), cottonseed meal (CSM) or cottonseed protein concentrate (CPC). After an 8-week feeding trial, fish were challenged by injection of Vibrio parahaemolyticus bacteria for 7 days until the fish stabilized. The results showed that the specific growth rate (SGR) of the FM group was higher than other groups. The SGR of the CPC group was higher than those of the SBM, PM and CSM groups. The catalase (CAT) contents in the serum of fish fed a plant protein diet were higher than in FM fish. The abundances of Rhodobacteraceae and Microbacteriaceae in the MI (mid intestine) were higher in the CPC group. The TLR-2 expressions in the MI and DI of plant protein-fed fish were up-regulated. The expressions of IL-6 in the PI and MI, of hepcidin and TLR-3 in the MI, and of TLR-3 in the DI, were all lower than those of fish fed FM. In the PI, MI and DI, the protein expressions of P-PI3K/T-PI3K in the SBM and PM groups were higher than in the FM group. After the challenge, the cumulative mortalities in the FM and CPC groups were lower than those of the SBM, PM and CSM groups. These results suggested that plant protein diets reduced antioxidant capacity and glycolipid metabolism, hindered the development of the intestine and reduced intestinal flora diversity. TLR-3 is involved in the immune regulation of the PI in CPC group, MI and DI in SBM, PM, CSM and CPC groups, while might be involved in the immune regulation of the PI in SBM, PM and CSM groups. Furthermore, PI3K/Akt signaling does not participate in the regulation of PI and MI in the CSM group, MI and DI in the CPC group.
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Affiliation(s)
- Bin Yin
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, 524025, China
| | - Hongyu Liu
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, 524025, China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, China
| | - Beiping Tan
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, 524025, China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, China.
| | - Xiaohui Dong
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, 524025, China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, China
| | - Shuyan Chi
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, 524025, China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, China
| | - Qihui Yang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, 524025, China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, China
| | - Shuang Zhang
- Laboratory of Aquatic Animal Nutrition and Feed, Fisheries College, Guangdong Ocean University, Zhanjiang, 524025, China; Aquatic Animals Precision Nutrition and High Efficiency Feed Engineering Research Centre of Guangdong Province, Zhanjiang, 524025, China; Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture, Zhanjiang, 524025, China
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Abstract
Adoptive T cell therapy has proven effective against hematologic malignancies and demonstrated efficacy against a variety of solid tumors in preclinical studies and clinical trials. Nonetheless, antitumor responses against solid tumors remain modest, highlighting the need to enhance the effectiveness of this therapy. Genetic modification of T cells with RNA has been explored to enhance T-cell antigen specificity, effector function, and migration to tumor sites, thereby potentiating antitumor immunity. This review describes the rationale for RNA-electroporated T cell modifications and provides an overview of their applications in preclinical and clinical investigations for the treatment of hematologic malignancies and solid tumors.
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Affiliation(s)
- Fernanda Pohl-Guimarães
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Lan B Hoang-Minh
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Duane A Mitchell
- Preston A. Wells, Jr. Center for Brain Tumor Therapy, UF Brain Tumor Immunotherapy Program, McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL, USA
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35
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Shang W, Xu R, Xu T, Wu M, Xu J, Wang F. Ovarian Cancer Cells Promote Glycolysis Metabolism and TLR8-Mediated Metabolic Control of Human CD4 + T Cells. Front Oncol 2020; 10:570899. [PMID: 33102225 PMCID: PMC7545320 DOI: 10.3389/fonc.2020.570899] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 08/27/2020] [Indexed: 01/07/2023] Open
Abstract
An immunosuppressive microenvironment is a major obstacle for successful tumor immunotherapy. Elucidating the regulatory mechanisms of energy metabolism and functionality in CD4+ T cells will provide insights for the development of novel immunotherapies for ovarian cancer (OC). An Agilent microarray was used to detect differences in gene expression between peripheral CD4+ T cells from five OC patients and those from five healthy controls. Functional pathway analysis was performed for differentially expressed genes. Gene expression profiles revealed significant differences in expression levels of 5,175 genes in peripheral CD4+ T cells from five patients with OC. Functional analysis indicated that the most significantly enriched pathways were metabolic pathways. Furthermore, eight glycolysis-related genes all showed significantly increased expression in peripheral CD4+ T cells of OC patients. Moreover, we established a coculture system of human CD4+ T cells with the OC cell line SKOV3, and then treated them with toll-like receptor 8 (TLR8) ligand ssRNA 40. Coculturing with SKOV3 cells could increase the expression of the eight glycolysis-related genes, promote glucose uptake and glycolysis in CD4+ T cells, induce the differentiation of CD4+ CD25+ Foxp3+ T cells, and enhance the suppression of naïve CD4+ T cells. Additionally, activated TLR8 signaling could mediate the reprogramming of glycolysis metabolism and function in CD4+ T cells. Overall, our study indicates that the SKOV3 coculture environment could regulate the glycolysis metabolism and function of CD4+ T cells, and also that TLR8 mediated the metabolic control of glycolysis in CD4+ T cells cocultured with SKOV3 cells. This provides a new direction for immunotherapy investigations in OC.
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Affiliation(s)
- Wenwen Shang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Rui Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Ting Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Ming Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
| | - Juan Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Clinical Laboratory, Taizhou People's Hospital, Taizhou, China
| | - Fang Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,National Key Clinical Department of Laboratory Medicine, Nanjing, China
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36
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Lee HG, Cho MZ, Choi JM. Bystander CD4 + T cells: crossroads between innate and adaptive immunity. Exp Mol Med 2020; 52:1255-1263. [PMID: 32859954 PMCID: PMC8080565 DOI: 10.1038/s12276-020-00486-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/21/2020] [Accepted: 06/15/2020] [Indexed: 12/11/2022] Open
Abstract
T cells are the central mediators of both humoral and cellular adaptive immune responses. Highly specific receptor-mediated clonal selection and expansion of T cells assure antigen-specific immunity. In addition, encounters with cognate antigens generate immunological memory, the capacity for long-term, antigen-specific immunity against previously encountered pathogens. However, T-cell receptor (TCR)-independent activation, termed “bystander activation”, has also been found. Bystander-activated T cells can respond rapidly and secrete effector cytokines even in the absence of antigen stimulation. Recent studies have rehighlighted the importance of antigen-independent bystander activation of CD4+ T cells in infection clearance and autoimmune pathogenesis, suggesting the existence of a distinct innate-like immunological function performed by conventional T cells. In this review, we discuss the inflammatory mediators that activate bystander CD4+ T cells and the potential physiological roles of these cells during infection, autoimmunity, and cancer. Immune cells that become activated in the absence of antigen stimulation could be harnessed in the fight against infection, autoimmunity, and cancer. Je-Min Choi and colleagues from Hanyang University in Seoul, South Korea, review how the immune system can deploy helper T cells through an unusual process called bystander activation. Most T cells become activated only after receptors on their surface bind to specific cognate antigen. In contrast, bystander T cells are activated non-specifically in response to cytokines and other pro-inflammatory mediators. Studies have shown that this cell population has a variety of protective and pathogenic functions, for example, guarding against multiple sclerosis, aggravating the symptoms of parasitic infections and promoting antitumor immunity. A better understanding of these immune cells could lead to new therapeutic options for these diseases.
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Affiliation(s)
- Hong-Gyun Lee
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea.,Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea
| | - Min-Zi Cho
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea.,Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea
| | - Je-Min Choi
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Republic of Korea. .,Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of Korea. .,Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul, Republic of Korea.
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Wu N, Chen D, Sun H, Tan J, Zhang Y, Zhang T, Han Y, Liu H, Ouyang X, Yang XD, Niu X, Zhong J, Wang Z, Su B. MAP3K2 augments Th1 cell differentiation via IL-18 to promote T cell-mediated colitis. SCIENCE CHINA-LIFE SCIENCES 2020; 64:389-403. [PMID: 32737854 DOI: 10.1007/s11427-020-1720-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022]
Abstract
T cell-mediated immunity in the intestine is stringently controlled to ensure proper immunity against pathogenic microbes and to prevent autoimmunity, a known cause of inflammatory bowel disease. However, precisely how T cells regulate intestine immunity remains to be fully understood. In this study, we found that mitogen-activated protein kinase kinase kinase 2 (MAP3K2) is required for the CD4+ T cell-mediated inflammation in the intestine. Using a T cell transfer colitis model, we found that MAP3K2-deficient naïve CD4 T cells had a dramatically reduced ability to induce colitis compared to wild type T cells. In addition, significantly fewer IFN-γ- but more IL-17A-producing CD4+ T cells in the intestines of mice receiving MAP3K2-deficient T cells than in those from mice receiving wild type T cells was observed. Interestingly, under well-defined in vitro differentiation conditions, MAP3K2-deficient naïve T cells were not impaired in their ability to differentiate into Th1, Th17 and Treg. Furthermore, the MAP3K2-regulated colitis severity was mediated by Th1 but not Th17 cells in the intestine. At the molecular level, we showed that MAP3K2-mediated Th1 cell differentiation in the intestine was regulated by IL-18 and required specific JNK activation. Together, our study reveals a novel regulatory role of MAP3K2 in intestinal T cell immunity via the IL-18-MAP3K2-JNK axis and may provide a novel target for intervention in T cell-mediated colitis.
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Affiliation(s)
- Ningbo Wu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
- Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Dongping Chen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
- Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Hongxiang Sun
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
- Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Jianmei Tan
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
- Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Yao Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Tianyu Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Yuheng Han
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
- Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Hongzhi Liu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
- Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Xinxing Ouyang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Xiao-Dong Yang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
- Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Xiaoyin Niu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Jie Zhong
- Department of Gastroenterology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China
| | - Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China.
| | - Bing Su
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China.
- Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China.
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38
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Gan Y, Ai G, Wu J, Luo H, Chen L, Huang Q, Wu X, Xu N, Li M, Su Z, Liu Y, Huang X. Patchouli oil ameliorates 5-fluorouracil-induced intestinal mucositis in rats via protecting intestinal barrier and regulating water transport. JOURNAL OF ETHNOPHARMACOLOGY 2020; 250:112519. [PMID: 31883475 DOI: 10.1016/j.jep.2019.112519] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/26/2019] [Accepted: 12/24/2019] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pogostemon cablin, commonly named "Guang-Huo-Xiang" in China, has long been renowned for its ability to dispel dampness and regulate gastrointestinal functions. Patchouli oil (P.oil), the major active fraction of Pogostemon cablin, has been traditionally used as the principal component of Chinese medicinal formulae to treat exterior syndrome and diarrhea. However, the effects of P.oil in treating 5-fluorouracil (5-FU)-induced intestinal mucositis have not yet been reported. AIM OF THE STUDY To investigate the protective effects of P.oil against 5-FU-induced intestinal mucositis and the mechanisms underlying these effects. MATERIALS AND METHODS Sprague-Dawley rats were intraperitoneally injected with 5-FU (30 mg/kg) to establish an intestinal mucositis model. Meanwhile, rats with intestinal mucositis were orally administered with P.oil (25, 50, and 100 mg/kg). Histological analysis, ELISA (for detecting inflammatory cytokines and aquaporins), immunohistochemistry analysis (for examining caspases), qRT-PCR analysis (for assessment tight junctions), and western blotting analysis (for the assessment of TLR2/TLR4-MyD88 and VIP-cAMP-PKA signaling pathway-related proteins) were performed to estimate the protective effects of P.oil against intestinal mucositis and the mechanisms underlying these effects. RESULTS The histopathological assessment preliminarily exhibited that P.oil alleviated the 5-FU-induced damage to the intestinal structure. After P.oil administration, the elevation of the expression of cytokines (TNF-α, IFN-γ, and IL-13) decreased markedly and the activation of NF-κB and MAPK signaling was significantly inhibited. P.oil also increased the mRNA expression of ZO-1 and Occludin, thereby stabilizing intestinal barrier. In addition, P.oil decreased the expressions of caspase-8, caspase-3, and Bax, and increased the expression of Bcl-2, thereby reducing the apoptosis of the intestinal mucosa. These results were closely related to the regulation of the TLR2/TLR4-MyD88 signaling pathway. It has been indicated that P.oil possibly protected the intestinal barrier by reducing inflammation and apoptosis. Furthermore, this study showed that P.oil inhibited the abnormal expression of AQP3, AQP7, and AQP11 by regulating the VIP-cAMP-PKA signaling pathway. Furthermore, it restored the intestinal water absorption, thereby alleviating diarrhea. CONCLUSIONS P.oil ameliorated 5-FU-induced intestinal mucositis in rats via protecting intestinal barrier and regulating water transport.
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Affiliation(s)
- Yuxuan Gan
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Gaoxiang Ai
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Jiazhen Wu
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Huijuan Luo
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Liping Chen
- Faculty of Health Sciences, University of Macau, Macao, China
| | - Qionghui Huang
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xue Wu
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Nan Xu
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Minyao Li
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Ziren Su
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Dongguan & Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Dongguan, 523808, China
| | - Yuhong Liu
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Xiaoqi Huang
- Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China; Dongguan & Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Dongguan, 523808, China.
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Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes. Cells 2020; 9:cells9030713. [PMID: 32183240 PMCID: PMC7140608 DOI: 10.3390/cells9030713] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 12/23/2022] Open
Abstract
Background: Human Vγ9Vδ2 γδ T cells can kill a variety of cancer cells and have attracted substantial interest for cancer immunotherapy. Toll-like receptor (TLR) ligands are promising adjuvants for cancer immunotherapy, but TLR7/8 ligand Resiquimod has been shown to inhibit CD4 T-cell activation in a monocyte-dependent manner. Therefore, we studied the modulation of human γδ T-cell activation by TLR7/8 ligands. Methods: Peripheral blood mononuclear cells (PBMC) or purified γδ T cells together with purified monocytes were stimulated with zoledronic acid or phosphoantigens in the absence or presence of various imidazoquinoline TLR7 or TLR8 agonists. Read-out systems included interferon-γ induction and cellular expansion of γδ T cells, as well as viability, cell surface antigen modulation, and IL-1β and TNF-α production of monocytes. Results: TLR8 ligand TL8-506 and TLR7/8 ligand Resiquimod (but not TLR7 ligands) rapidly induced IFN-γ expression in γδ T cells within PBMC, and co-stimulated phosphoantigen-induced IFN-γ expression in γδ T cells. On the other hand, TLR8 ligands potently suppressed γδ T-cell expansion in response to zoledronic acid and phosphoantigen. Purified monocytes secreted large amounts of IL-1β and TNF-α when stimulated with TLR8 ligands but simultaneously underwent substantial cell death after 24 h. Conclusions: TLR8 ligand-activated monocytes potently co-stimulate early γδ T-cell activation but failed to provide accessory cell function for in vitro expansion of γδ T cells.
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Meås HZ, Haug M, Beckwith MS, Louet C, Ryan L, Hu Z, Landskron J, Nordbø SA, Taskén K, Yin H, Damås JK, Flo TH. Sensing of HIV-1 by TLR8 activates human T cells and reverses latency. Nat Commun 2020; 11:147. [PMID: 31919342 PMCID: PMC6952430 DOI: 10.1038/s41467-019-13837-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 12/02/2019] [Indexed: 12/31/2022] Open
Abstract
During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.
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Affiliation(s)
- Hany Zekaria Meås
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway
| | - Markus Haug
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway
| | - Marianne Sandvold Beckwith
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Claire Louet
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Liv Ryan
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Zhenyi Hu
- School of Pharmaceutical Sciences, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, 100082, Beijing, China.,Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Johannes Landskron
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Svein Arne Nordbø
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Medical Microbiology, St. Olavs Hospital, Trondheim, Norway
| | - Kjetil Taskén
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.,Department of Cancer Immunology, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Hang Yin
- School of Pharmaceutical Sciences, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, 100082, Beijing, China
| | - Jan Kristian Damås
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway
| | - Trude Helen Flo
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. .,Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway. .,Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
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The activation of bystander CD8 + T cells and their roles in viral infection. Exp Mol Med 2019; 51:1-9. [PMID: 31827070 PMCID: PMC6906361 DOI: 10.1038/s12276-019-0316-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/09/2019] [Accepted: 07/05/2019] [Indexed: 02/06/2023] Open
Abstract
During viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as "bystander activation." Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.
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Werts C. Interaction of Leptospira with the Innate Immune System. Curr Top Microbiol Immunol 2019; 415:163-187. [PMID: 29038956 DOI: 10.1007/82_2017_46] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Innate immunity encompasses immediate host responses that detect and respond to microbes. Besides recognition by the complement system (see the chapter by A. Barbosa, this volume), innate immunity concerns cellular responses. These are triggered through recognition of conserved microbial components (called MAMPs) by pattern recognition receptors (PRRs), leading, through secretion of cytokines, antimicrobial peptides, and immune mediators, to cellular recruitment and phagocytosis. Leptospira spp. are successful zoonotic pathogenic bacteria that obviously overcome the immune system of their hosts. The first part of this chapter summarizes what is known about leptospires recognition and interaction with phagocytes and other innate immune cells, and the second part describes specific interactions of leptospiral MAMPs with PRRs from the TLR and NLR families. On the one hand, pathogenic leptospires appear to escape macrophage and neutrophil phagocytosis. On the other hand, studies about PRR sensing of leptospires remain very limited, but suggest that pathogenic leptospires escape some of the PRRs in a host-specific manner, due to peculiar cell wall specificities or post-translational modifications that may impair their recognition. Further studies are necessary to clarify the mechanisms and consequences of leptospiral escape on phagocytic functions and hopefully give clues to potential therapeutic strategies aimed at restoring the defective activation of PRRs by pathogenic Leptospira spp.
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Affiliation(s)
- Catherine Werts
- Unité Biologie et Génétique de La Paroi Bactérienne, Institut Pasteur, Paris, France.
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The Innate Immune Sensor NLRC3 Acts as a Rheostat that Fine-Tunes T Cell Responses in Infection and Autoimmunity. Immunity 2019; 49:1049-1061.e6. [PMID: 30566882 DOI: 10.1016/j.immuni.2018.10.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 08/12/2018] [Accepted: 10/03/2018] [Indexed: 12/31/2022]
Abstract
Appropriate immune responses require a fine balance between immune activation and attenuation. NLRC3, a non-inflammasome-forming member of the NLR innate immune receptor family, attenuates inflammation in myeloid cells and proliferation in epithelial cells. T lymphocytes express the highest amounts of Nlrc3 transcript where its physiologic relevance is unknown. We show that NLRC3 attenuated interferon-γ and TNF expression by CD4+ T cells and reduced T helper 1 (Th1) and Th17 cell proliferation. Nlrc3-/- mice exhibited increased and prolonged CD4+ T cell responses to lymphocytic choriomeningitis virus infection and worsened experimental autoimmune encephalomyelitis (EAE). These functions of NLRC3 were executed in a T-cell-intrinsic fashion: NLRC3 reduced K63-linked ubiquitination of TNF-receptor-associated factor 6 (TRAF6) to limit NF-κB activation, lowered phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and diminished glycolysis and oxidative phosphorylation. This study reveals an unappreciated role for NLRC3 in attenuating CD4+ T cell signaling and metabolism.
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Cheng L, Tang X, Xu L, Zhang L, Shi H, Peng Q, Zhao F, Zhou Y, He Y, Wang H, Zhou B, Gao Z, Chen Z. Interferon-γ upregulates Δ42PD1 expression on human monocytes via the PI3K/AKT pathway. Immunobiology 2019; 224:388-396. [PMID: 30846331 DOI: 10.1016/j.imbio.2019.02.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 02/14/2019] [Accepted: 02/19/2019] [Indexed: 01/03/2023]
Abstract
BACKGROUND We recently identified a novel alternatively spliced isoform of human programmed cell death 1 (PD-1), named Δ42PD1, which contains a 42-base-pair in-frame deletion compared with the full-length PD-1. Δ42PD1 is likely constitutively expressed on human monocytes and down-regulated in patients infected with human immunodeficiency virus type 1 (HIV-1). The mechanism underlying the regulation of Δ42PD-1 expression in monocytes remains unknown. METHODS By flow cytometry, we investigated the effect of Interferon-gamma (INF-γ) on the expression of Δ42PD1 in primary human monocytes as well as monocytic cell lines THP-1 and U937 cells. In addition, signaling pathway inhibitors and Δ42PD1-specific blocking antibody were used to explore the pathway involved in INF-γ-induced Δ42PD1 upregulation, and to elucidate the relationship between Δ42PD1 and TNF-α or IL-6 production by INF-γ primed monocytes in response to pre-fixed E. coli. Furthermore, we assessed T-cell proliferation, activation and cytokine production as enriched CD4+ T cells were co-cultured with THP-1 or U937 cells, with or without Δ42PD1-blocking antibody. RESULTS Treatment of human peripheral blood mononuclear cells (PBMCs) with IFN-γ resulted in an approximately 4-fold increase in the expression of Δ42PD1 on monocytes. Similarly, IFN-γ upregulates Δ42PD1 expression on human monocytic cell lines THP-1 and U937, in a time- and dose-dependent manner. IFN-γ-induced Δ42PD1 upregulation was abolished by JAK inhibitors Ruxolitinib and Tasocitinib, PI3K inhibitor LY294002, and AKT inhibitor MK-2206, respectively, but not by STAT1 inhibitor and MAPK signaling pathway inhibitors. JAK, PI3K-AKT, and MAPK signaling inhibitors abolished effectively the production of TNF-α and IL-6 in INF-γ-primed monocytes in response to pre-fixed E. coli. In contrast, Δ42PD1-specific blocking antibody did not affect the IFN-γ-induced priming effect. Furthermore, the MFI ratio of Δ42PD1 to full-length PD-1 (PD-1 Δ/F ratio) was significantly and positively correlated with TNF-α (P = 0.0289, r = 0.6038) produced by circulating CD14+ monocytes in response to pre-fixed E. coli. Notably, Δ42PD1 blockage significantly inhibited CD4+ T-cells proliferation and cytokine production in the co-culture conditions. CONCLUSIONS We demonstrated that IFN-γ increases Δ42PD1 expression on human monocytes via activating the PI3K/AKT signaling pathway downstream of JAKs, and that the PD-1 Δ/F ratio is a potential biomarker to predict the functional state of monocytes. Notably, we revealed the Δ42PD1 play a role in T-cell regulation, providing a novel potential approach to manipulate adaptive immune response.
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Affiliation(s)
- Lin Cheng
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China; HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Xian Tang
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Liumei Xu
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Lukun Zhang
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Huichun Shi
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Qiaoli Peng
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Fang Zhao
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Yang Zhou
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Yun He
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Hui Wang
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Boping Zhou
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Zhiliang Gao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Zhiwei Chen
- HKU-AIDS Institute Shenzhen Research Laboratory, Shenzhen Key Laboratory of Infection and Immunity, Guangdong Key Laboratory of Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China; AIDS Institute, Research Center for Infection and Immunity, Department of Microbiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
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Motedayyen H, Fathi F, Fasihi-Ramandi M, Sabzghabaee AM, Taheri RA. Toll-like receptor 4 activation on human amniotic epithelial cells is a risk factor for pregnancy loss. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2019; 24:1. [PMID: 30815014 PMCID: PMC6383334 DOI: 10.4103/jrms.jrms_463_18] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/25/2018] [Accepted: 09/26/2018] [Indexed: 12/24/2022]
Abstract
Background: Maternal–fetal tolerance plays a fundamental role in the maintenance of pregnancy. However, this immunological tolerance can be influenced by intrauterine infections. Human amniotic epithelial cells (hAECs) have immunomodulatory effects and respond to invading pathogens through expressing various toll-like receptors (TLRs). We hypothesize that bacteria or bacterial products affect the immunosuppressive effects of hAECs through TLR stimulation. Here, we investigated how a successful pregnancy can be threatened by TLR4 activation on hAECs on lipopolysaccharide (LPS) engagement. Materials and Methods: hAECs were isolated from the amniotic membrane received from six healthy pregnant women. The immunophenotyping of hAECs was studied by flow cytometry. The isolated hAECs (4 × 105 cells/ml) were cultured in 24-well plates in the presence or absence of LPS (5 μg/ml). After 24, 48, and 72 h of incubation, the culture supernatants of hAECs were collected, and the levels of interleukin-5 (IL-5), IL-6, IL-1β, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1), and prostaglandin E2 (PGE2) were measured by enzyme-linked immunosorbent assay. Results: TLR4 activation showed a stimulatory effect on TGF-β1 production of hAECs (P < 0.001–0.05). PGE2 production of LPS-stimulated hAECs was significantly increased (P < 0.01–0.05). Moreover, TLR4 could induce TNF-α and IL-1β production of hAECs (P < 0.0001–0.01), while this effect was not observed on IL-6 production of hAECs. The IL-5 was produced at a very low level in two culture supernatants of hAECs, in which its production was independent of LPS effect. Conclusion: TLR4 activation by bacterial components on hAECs may be a potential risk factor for pregnancy complications.
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Affiliation(s)
- Hossein Motedayyen
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Farshid Fathi
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahdi Fasihi-Ramandi
- Molecular Biology Research Center, System Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ali Mohammad Sabzghabaee
- Isfahan Clinical Toxicology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ramezan Ali Taheri
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Activation of natural killer T cells contributes to triptolide-induced liver injury in mice. Acta Pharmacol Sin 2018; 39:1847-1854. [PMID: 30013034 DOI: 10.1038/s41401-018-0084-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/19/2018] [Indexed: 12/24/2022]
Abstract
Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 μg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers. However, the mice were resistant to the development of TP-induced liver injury when their NKT cells were depleted by injection of anti-NK1.1 mAb (200 μg, i.p.) on days -2 and -1 before TP administration. We further revealed that TP administration activated NKT cells, dominantly releasing Th1 cytokine IFN-γ, recruiting neutrophils and macrophages, and leading to liver damage. After anti-NK1.1 injection, however, the mice mainly secreted Th2 cytokine IL-4 in the livers and exhibited a significantly lower percentage of hepatic infiltrating neutrophils and macrophages upon TP challenge. The activation of NKT cells was associated with the upregulation of Toll-like receptor (TLR) signaling pathway. Collectively, these results demonstrate a novel role of NKT cells contributing to the mechanisms of TP-induced liver injury. More importantly, the regulation of NKT cells may promote effective measures that control drug-induced liver injury.
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Bystander T Cells: A Balancing Act of Friends and Foes. Trends Immunol 2018; 39:1021-1035. [PMID: 30413351 DOI: 10.1016/j.it.2018.10.003] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 09/27/2018] [Accepted: 10/04/2018] [Indexed: 02/07/2023]
Abstract
T cell responses are essential for appropriate protection against pathogens. T cell immunity is achieved through the ability to discriminate between foreign and self-molecules, and this relies heavily on stringent T cell receptor (TCR) specificity. Recently, bystander activated T lymphocytes, that are specific for unrelated epitopes during an antigen-specific response, have been implicated in diverse diseases. Numerous infection models have challenged the classic dogma of T cell activation as being solely dependent on TCR and major histocompatibility complex (MHC) interactions, indicating an unappreciated role for pathogen-associated receptors on T cells. We discuss here the specific roles of bystander activated T cells in pathogenesis, shedding light on the ability of these cells to modulate disease severity independently from TCR recognition.
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Ding C, Li L, Zhang Y, Ji Z, Zhang C, Liang T, Guo X, Liu X, Kang Q. Toll-like receptor agonist rMBP-NAP enhances antitumor cytokines production and CTL activity of peripheral blood mononuclear cells from patients with lung cancer. Oncol Lett 2018; 16:4707-4712. [PMID: 30214604 PMCID: PMC6126164 DOI: 10.3892/ol.2018.9182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 05/30/2018] [Indexed: 11/06/2022] Open
Abstract
Toll-like receptor (TLR) agonists are known for their ability to inhibit tumor progression via enhancing antitumor cytokines production and cytotoxic T lymphocyte (CTL) activity. Recombinant Helicobacter pylori neutrophil-activating protein fused with maltose-binding protein (rMBP-NAP) has been reported as a novel TLR agonist for antitumor treatment in murine models. The present study aimed to determine the potential and efficacy of the rMBP-NAP for antitumor treatment prior to further clinical trials. The rMBP-NAP was expressed and purified for subsequent experiments. Peripheral blood mononuclear cells (PBMCs) from health donors and patients with lung cancer (LC) were incubated with PBS and 0.2 mg/ml rMBP-NAP. Antitumor cytokines production was assayed using ELISA and reverse transcription-quantitative polymerase chain reaction analysis. The cytolytic activity of PBMCs and the number of Interferon-γ (IFN-γ)-secreting cells were assayed using lactate dehydrogenase and Enzyme-linked ImmunoSpot assays, respectively. The results from the present study revealed that the expression of IFN-γ, interleukin (IL)-2, tumor necrosis factor-α and IL-12 of PBMCs from patients with LC and healthy donors were significantly increased following treatment with rMBP-NAP (P<0.05). Additionally, rMBP-NAP significantly upregulated the number of IFN-γ-secreting cells in PBMCs and prominently increased the cytotoxic activity of PBMCs (P<0.05). Furthermore, the expression of TLR2 was significantly enhanced following rMBP-NAP stimulation (P<0.05), which indicated that rMBP-NAP may serve an antitumor role via TLR2 signaling pathways. Overall, these results demonstrated that rMBP-NAP possesses the potential to be a novel immunomodulatory candidate drug and requires further evaluation in clinical trials.
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Affiliation(s)
- Cong Ding
- Department of Protein Function and Immunomodulatory Laboratory, School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Li Li
- Department of Protein Function and Immunomodulatory Laboratory, School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Yi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhenyu Ji
- Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Chenglong Zhang
- Department of Protein Function and Immunomodulatory Laboratory, School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Taotao Liang
- Department of Protein Function and Immunomodulatory Laboratory, School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xun Guo
- Department of Protein Function and Immunomodulatory Laboratory, School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xin Liu
- Department of Protein Function and Immunomodulatory Laboratory, School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Qiaozhen Kang
- Department of Protein Function and Immunomodulatory Laboratory, School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
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The effect of lipopolysaccharide on anti-inflammatory and pro-inflammatory cytokines production of human amniotic epithelial cells. Reprod Biol 2018; 18:404-409. [PMID: 30220549 DOI: 10.1016/j.repbio.2018.09.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 08/17/2018] [Accepted: 09/08/2018] [Indexed: 12/18/2022]
Abstract
Intrauterine infection is a major cause of immune imbalance at the maternal-fetal interface, which leads to spontaneous abortion, premature rupture of the fetal membranes, and preterm birth. Human amniotic epithelial cells (hAECs) play a fundamental role in the maintenance of pregnancy. We hypothesize that bacteria influence the immunomodulatory effects of hAECs through stimulation of Toll-like receptors (TLRs). Here, we investigated how lipopolysaccharide (LPS) as a bacterial component affects anti-inflammatory and pro-inflammatory cytokines production of hAECs. Human placentas were obtained from six healthy pregnant women and hAECs were isolated. The phenotypic characteristics of hAECs were determined by flow cytometry. The hAECs (4 × 105 cells/ml) were cultured in the presence or absence of LPS (5 μg/ml). The viability of the cells was assessed and culture supernatants of hAECs were collected after 24, 48 and 72 h of incubation. The levels of transforming growth factor-beta1 (TGF-β1), interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-α), interleukin-17 A (IL-17A), and interferon-gamma (IFN-γ) were measured by ELISA. Our data showed that LPS treatment did not affect the viability of hAECs, while had a stimulatory effect on TGF-β1 production of hAECs (p < 0.001). A significant reduction in IL-4 production of LPS-stimulated hAECs was observed (p < 0.05). LPS enhanced the production of TNF-α and IL-17 A of hAECs (p < 0.05-0.0001). The IFN-γ level was only detectable in two culture supernatants of hAECs, and the level was unchanged after stimulation with LPS. Based on these findings, LPS may play a pivotal role in immune imbalance at the feto-maternal interface through affecting anti-inflammatory and pro-inflammatory cytokines production of hAECs.
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Habtamu M, Abebe M, Aseffa A, Dyrhol-Riise AM, Spurkland A, Abrahamsen G. In vitro analysis of antigen induced T cell-monocyte conjugates by imaging flow cytometry. J Immunol Methods 2018; 460:93-100. [PMID: 29981305 DOI: 10.1016/j.jim.2018.06.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 06/20/2018] [Accepted: 06/25/2018] [Indexed: 12/13/2022]
Abstract
There is a lack of suitable correlates of immune protection against Mycobacterium tuberculosis (Mtb) infection. T cells and monocytes play key roles in host immunity against Mtb. Thus, a method that allows assessing their interaction would contribute to the understanding of immune regulation in tuberculosis (TB). We have established imaging flow cytometer (IFC) based in vitro assay for the analysis of early events in T cell-monocyte interaction, upstream of cytokine production and T cell proliferation. This was achieved through short term stimulation of peripheral blood mononuclear cells (PBMC) from healthy Norwegian blood donors with Mycobacterium bovis Bacille Calmette-Guérin (BCG). In our assay, we examined the kinetics of BCG uptake by monocytes using fluorescently labeled BCG and T cell-monocyte interaction based on synapse formation (CD3/TCR polarization). Our results showed that BCG stimulation induced a gradual increase in the proportion of conjugated T cells displaying NF-κB translocation to the nucleus in a time dependent manner, with the highest frequency observed at 6 h. We subsequently tested PBMC from a small cohort of active TB patients (n = 7) and observed a similar BCG induced NF-κB translocation in T cells conjugated with monocytes. The method allowed for simultaneous evaluation of T cell-monocyte conjugates and T cell activation as measured by NF-κB translocation, following short-term challenge of human PBMC with BCG. Whether this novel approach could serve as a diagnostic or prognostic marker needs to be investigated using a wide array of Mtb specific antigens in a larger cohort of patients with different TB infection status.
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Affiliation(s)
- Meseret Habtamu
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Norway; Armauer Hansen Research Institute, Addis Ababa, Ethiopia
| | - Markos Abebe
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
| | - Abraham Aseffa
- Armauer Hansen Research Institute, Addis Ababa, Ethiopia
| | - Anne Margarita Dyrhol-Riise
- Department of Infectious Disease, Oslo University Hospital, N-0424 Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway; Department of Clinical Science, Faculty of Medicine, University of Bergen, N-5020 Bergen, Norway
| | - Anne Spurkland
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Norway
| | - Greger Abrahamsen
- Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Norway.
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