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1
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Wu W, Cheng Z, Nan Y, Pan G, Wang Y. L-selectin Promotes Migration, Invasion and Inflammatory Response of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via NF-kB Signaling Pathway. Inflammation 2025:10.1007/s10753-025-02242-3. [PMID: 39821520 DOI: 10.1007/s10753-025-02242-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/28/2024] [Accepted: 01/08/2025] [Indexed: 01/19/2025]
Abstract
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by chronic inflammation of the synovium and progressive joint damage. Fibroblast-like synoviocytes (FLSs) exhibit excessive proliferative and aggressive phenotypes and play a major role in the pathophysiology of RA. Previous studies have confirmed the pathologic role of L-selectin in cell adhesion and migration. In rheumatoid arthritis models, L-selectin regulates leukocyte homing, which leads to joint inflammation. Moreover, in L-selectin knockout mice, there is a reduction in joint inflammation. However, the associations of L-selectin with FLSs in RA remain unclear. This study aims to reveal the effect of L-selectin on RA-FLSs and to investigate the molecular mechanism of L-selectin in RA. Our findings indicated that L-selectin was significantly expressed in RA synovial tissues and RA-FLSs. L-selectin silencing reduced RA-FLSs migration and invasion and attenuated the secretion of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in vitro. Moreover, investigations into mechanisms revealed that L-selectin activated the nuclear factor kappa-B (NF-κB) signaling pathway while blocking this signaling pathway could compromise the effects of L-selectin. Finally, in vivo experiments with a collagen-induced arthritis rat model revealed that silencing L-selectin alleviated inflammatory infiltration of the synovium and cartilage destruction, and validated the NF-κB signaling pathways findings observed in vitro. In summary, we show that L-selectin enhances the migration and invasion of RA-FLSs through the activation of NF-κB signaling pathways, ultimately worsening the progression of RA.
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Affiliation(s)
- Weijie Wu
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
- Department of Orthopaedics, Affiliated Nantong Hospital of Shanghai University, The Six People's Hospital of Nantong, Nantong, 226001, Jiangsu, China
| | - Zhen Cheng
- Department of Orthopaedics (Sports Medicine), Yancheng Third People's Hospital, Yancheng, 224000, Jiangsu, China
| | - Yunyi Nan
- Department of Pain Medicine, Yueqing People's Hospital, Affiliated Yueqing Hospital of Wenzhou Medical University, Wenzhou, 325600, Zhejiang, China
| | - Gang Pan
- Department of Orthopaedics, Affiliated Nantong Hospital of Shanghai University, The Six People's Hospital of Nantong, Nantong, 226001, Jiangsu, China.
| | - Youhua Wang
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China.
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2
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Hardtke-Wolenski M, Landwehr-Kenzel S. Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both? Mol Cell Pediatr 2024; 11:3. [PMID: 38507159 PMCID: PMC10954601 DOI: 10.1186/s40348-024-00176-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 03/07/2024] [Indexed: 03/22/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.
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Affiliation(s)
- Matthias Hardtke-Wolenski
- Hannover Medical School, Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
- University Hospital Essen, Institute of Medical Microbiology, University Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Department of Pediatric Pneumology, Allergology and Neonatology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
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3
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Fallahi F, Borran S, Ashrafizadeh M, Zarrabi A, Pourhanifeh MH, Khaksary Mahabady M, Sahebkar A, Mirzaei H. Curcumin and inflammatory bowel diseases: From in vitro studies to clinical trials. Mol Immunol 2020; 130:20-30. [PMID: 33348246 DOI: 10.1016/j.molimm.2020.11.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBDs) may result from mutations in genes encoding for innate immunity, which can lead to exacerbated inflammatory response. Although some mono-targeted treatments have developed in recent years, IBDs are caused through several pathway perturbations. Therefore, targeting all these pathways is difficult to be achieved by a single agent. Moreover, those mono-targeted therapies are usually expensive and may cause side-effects. These limitations highlight the significance of an available, inexpensive and multi-targeted dietary agents or natural compounds for the treatment and prevention of IBDs. Curcumin is a multifunctional phenolic compound that is known for its anti-inflammatory and immunomodulatory properties. Over the past decades, mounting experimental investigations have revealed the therapeutic potential of curcumin against a broad spectrum of inflammatory diseases including IBDs. Furthermore, it has been reported that curcumin directly interacts with many signaling mediators implicated in the pathogenesis of IBDs. These preclinical findings have created a solid basis for the assessment of the efficacy of curcumin in clinical practice. In clinical trials, different dosages e.g., 550 mg /three times daily-1month, and 1 g /twice times daily-6month of curcumin were used for patients with IBDs. Taken together, these findings indicated that curcumin could be employed as a therapeutic candidate in the treatment of IBDs. Moreover, it seems that overcome to current limitations of curcumin i.e., poor oral bioavailability, and poor oral absorption with using nanotechnology and others, could improve the efficacy of curcumin both in pre-clinical and clinical studies.
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Affiliation(s)
- Farzaneh Fallahi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Sarina Borran
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Istanbul, Turkey
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, 34956, Istanbul, Turkey
| | | | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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4
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Stockis J, Roychoudhuri R, Halim TYF. Regulation of regulatory T cells in cancer. Immunology 2019; 157:219-231. [PMID: 31032905 PMCID: PMC6587396 DOI: 10.1111/imm.13064] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/05/2019] [Accepted: 04/09/2019] [Indexed: 12/28/2022] Open
Abstract
The inflammatory response to transformed cells forms the cornerstone of natural or therapeutically induced protective immunity to cancer. Regulatory T (Treg) cells are known for their critical role in suppressing inflammation, and therefore can antagonize effective anti-cancer immune responses. As such, Treg cells can play detrimental roles in tumour progression and in the response to both conventional and immune-based cancer therapies. Recent advances in our understanding of Treg cells reveal complex niche-specific regulatory programmes and functions, which are likely to extrapolate to cancer. The regulation of Treg cells is reliant on upstream cues from haematopoietic and non-immune cells, which dictates their genetic, epigenetic and downstream functional programmes. In this review we will discuss how Treg cells are themselves regulated in normal and transformed tissues, and the implications of this cross talk on tumour growth.
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Affiliation(s)
- Julie Stockis
- CRUK Cambridge InstituteUniversity of CambridgeCambridgeUK
| | - Rahul Roychoudhuri
- Laboratory of Lymphocyte Signalling and DevelopmentThe Babraham InstituteCambridgeUK
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5
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Peng Q, Ratnasothy K, Boardman DA, Jacob J, Tung SL, McCluskey D, Smyth LA, Lechler RI, Dorling A, Lombardi G. Protease Activated Receptor 4 as a Novel Modulator of Regulatory T Cell Function. Front Immunol 2019; 10:1311. [PMID: 31275306 PMCID: PMC6591367 DOI: 10.3389/fimmu.2019.01311] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/23/2019] [Indexed: 01/19/2023] Open
Abstract
Regulatory T cells (Tregs) are a subpopulation of T cells that maintain immunological tolerance. In inflammatory responses the function of Tregs is tightly controlled by several factors including signaling through innate receptors such as Toll like receptors and anaphylatoxin receptors allowing an effective immune response to be generated. Protease-activated receptors (PARs) are another family of innate receptors expressed on multiple cell types and involved in the pathogenesis of autoimmune disorders. Whether proteases are able to directly modulate Treg function is unknown. Here, we show using two complimentary approaches that signaling through PAR-4 influences the expression of CD25, CD62L, and CD73, the suppressive capacity, and the stability of Tregs, via phosphorylation of FoxO1 and negative regulation of PTEN and FoxP3. Taken together, our results demonstrate an important role of PAR4 in tuning the function of Tregs and open the possibility of targeting PAR4 to modulate immune responses.
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Affiliation(s)
- Qi Peng
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
| | - Kulachelvy Ratnasothy
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
| | - Dominic A Boardman
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
| | - Jacinta Jacob
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
| | - Sim Lai Tung
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
| | - Daniel McCluskey
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom
| | - Lesley A Smyth
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,School of Health, Sport and Bioscience, University of East London, London, United Kingdom
| | - Robert I Lechler
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
| | - Anthony Dorling
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
| | - Giovanna Lombardi
- MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.,NIHR Biomedical Research Centre, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, King's College London, London, United Kingdom
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6
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Dios-Esponera A, Melis N, Subramanian BC, Weigert R, Samelson LE. Pak1 Kinase Promotes Activated T Cell Trafficking by Regulating the Expression of L-Selectin and CCR7. Front Immunol 2019; 10:370. [PMID: 30891040 PMCID: PMC6411651 DOI: 10.3389/fimmu.2019.00370] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 02/13/2019] [Indexed: 01/13/2023] Open
Abstract
Normal function of the adaptive immune system requires trafficking of T cells between the blood and lymphoid organs. Lymphocyte homing to lymph nodes requires that they cross endothelial barriers present in blood vessels and lymphatics. This multi-step process requires a remodeling of the lymphocyte plasma membrane, which is mediated by the dynamic re-arrangement of the actin cytoskeleton. Pak1 plays a central role in cell morphology, adhesion and migration in various cell types. Here we demonstrate that Pak1 is required for activated CD4+ T cell trafficking to lymph nodes. Pak1 deficiency in T cells causes a defect in the transcription of CCR7 and L-selectin, thereby altering lymphocyte trafficking. Additionally, we report an increase in L-selectin shedding in Pak1-deficient T cells, which correlates with a decrease in the recruitment of calmodulin to the cytoplasmic tail of L-selectin during T cell activation. Overall, our findings demonstrate that by regulating the expression of two major lymph node homing molecules, L-selectin and CCR7, Pak1 mediates activated CD4+ T cell trafficking.
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Affiliation(s)
- Ana Dios-Esponera
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Nicolas Melis
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Bhagawat C Subramanian
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Roberto Weigert
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Lawrence E Samelson
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
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7
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Egress of murine regulatory T cells from the thymus requires TIPE2. Biochem Biophys Res Commun 2018; 500:376-383. [DOI: 10.1016/j.bbrc.2018.04.082] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 04/10/2018] [Indexed: 12/22/2022]
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8
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Lee JJ, Kao KC, Chiu YL, Jung CJ, Liu CJ, Cheng SJ, Chang YL, Ko JY, Chia JS. Enrichment of Human CCR6 + Regulatory T Cells with Superior Suppressive Activity in Oral Cancer. THE JOURNAL OF IMMUNOLOGY 2017; 199:467-476. [PMID: 28600287 DOI: 10.4049/jimmunol.1601815] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 05/12/2017] [Indexed: 01/29/2023]
Abstract
Human oral squamous cell carcinoma (OSCC) constitutes an inflammatory microenvironment enriched with chemokines such as CCL20, which promote cancer cell invasion and tumor progression. We found that in OSCC there is a correlation between the expression of CCL20 and FOXP3 mRNA. Therefore, we hypothesized that OSCC may favor the recruitment and retention of regulatory T (Treg) cells that express the CCL20 receptor, CCR6. Interestingly, most (∼60%) peripheral blood Treg cells express CCR6, and CCR6+ Treg cells exhibit an activated effector/memory phenotype. In contrast, a significant portion (>30%) of CCR6- Treg cells were found to be CD45RA+ naive Treg cells. Compared to CCR6- naive or memory Treg cells, CCR6+ Treg cells exhibit stronger suppressive activity and display higher FOXP3 expression along with lower methylation at the Treg-specific demethylated region of the FOXP3 gene. This predominance of CCR6+ Treg cells was also found in the draining lymph nodes and tumor-infiltrating lymphocytes of OSCC patients with early or late clinical staging. Moreover, CCR6+ Treg cells isolated from tumor-infiltrating lymphocytes or draining lymph nodes maintained similar phenotypic and suppressive characteristics ex vivo as did their counterparts isolated from peripheral blood. These results suggest that CCR6 marks activated effector or memory Treg phenotypes with superior suppressive activity in humans.
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Affiliation(s)
- Jang-Jaer Lee
- Department of Oral Maxillofacial Surgery, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Kung-Chi Kao
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Yen-Ling Chiu
- Department of Nephrology, Far Eastern Memorial Hospital, Taipei 220, Taiwan.,Graduate Program of Biomedical Informatics, Yuan Ze University, Taoyuan 320, Taiwan
| | - Chiau-Jing Jung
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Chung-Ji Liu
- Department of Oral Maxillofacial Surgery, Taipei MacKay Memorial Hospital, Taipei 104, Taiwan
| | - Shih-Jung Cheng
- Department of Oral Maxillofacial Surgery, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Yen-Liang Chang
- Department of Otolaryngology, Fu Jen Catholic University College of Medicine, New Taipei City 24205, Taiwan; and
| | - Jenq-Yuh Ko
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 100, Taiwan
| | - Jean-San Chia
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei 100, Taiwan;
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9
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Fu H, Ward EJ, Marelli-Berg FM. Mechanisms of T cell organotropism. Cell Mol Life Sci 2016; 73:3009-33. [PMID: 27038487 PMCID: PMC4951510 DOI: 10.1007/s00018-016-2211-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 03/21/2016] [Accepted: 03/22/2016] [Indexed: 02/06/2023]
Abstract
Protective immunity relies upon T cell differentiation and subsequent migration to target tissues. Similarly, immune homeostasis requires the localization of regulatory T cells (Tregs) to the sites where immunity takes place. While naïve T lymphocytes recirculate predominantly in secondary lymphoid tissue, primed T cells and activated Tregs must traffic to the antigen rich non-lymphoid tissue to exert effector and regulatory responses, respectively. Following priming in draining lymph nodes, T cells acquire the 'homing receptors' to facilitate their access to specific tissues and organs. An additional level of topographic specificity is provided by T cells receptor recognition of antigen displayed by the endothelium. Furthermore, co-stimulatory signals (such as those induced by CD28) have been shown not only to regulate T cell activation and differentiation, but also to orchestrate the anatomy of the ensuing T cell response. We here review the molecular mechanisms supporting trafficking of both effector and regulatory T cells to specific antigen-rich tissues.
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Affiliation(s)
- Hongmei Fu
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Eleanor Jayne Ward
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Federica M Marelli-Berg
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
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10
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Yamada A, Arakaki R, Saito M, Tsunematsu T, Kudo Y, Ishimaru N. Role of regulatory T cell in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2016; 22:2195-205. [PMID: 26900284 PMCID: PMC4734996 DOI: 10.3748/wjg.v22.i7.2195] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 11/11/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
Regulatory T (Treg) cells play key roles in various immune responses. For example, Treg cells contribute to the complex pathogenesis of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis during onset or development of that disease. Many animal models of IBD have been used to investigate factors such as pathogenic cytokines, pathogenic bacteria, and T-cell functions, including those of Treg cells. In addition, analyses of patients with IBD facilitate our understanding of the precise mechanism of IBD. This review article focuses on the role of Treg cells and outlines the pathogenesis and therapeutic strategies of IBD based on previous reports.
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11
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Fukazawa T, Hiraiwa N, Umemura T, Mise-Omata S, Obata Y, Doi T. Egress of Mature Murine Regulatory T Cells from the Thymus Requires RelA. THE JOURNAL OF IMMUNOLOGY 2015; 194:3020-8. [DOI: 10.4049/jimmunol.1302756] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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12
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Tucker RM, Feldman AG, Fenner EK, Mack CL. Regulatory T cells inhibit Th1 cell-mediated bile duct injury in murine biliary atresia. J Hepatol 2013; 59:790-6. [PMID: 23685050 PMCID: PMC3855478 DOI: 10.1016/j.jhep.2013.05.010] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 04/30/2013] [Accepted: 05/03/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Biliary atresia (BA) is a pediatric inflammatory disease of the biliary system which leads to cirrhosis and the need for liver transplantation. One theory regarding etiology is that bile duct injury is due to virus-induced autoreactive T cell-mediated inflammation. Regulatory T cell (Treg) abnormalities in BA could result in unchecked bystander inflammation and autoimmunity targeting bile ducts. The aim of this study was to determine if Tregs are dysfunctional in the rotavirus-induced mouse model of BA (murine BA). METHODS Murine BA resulted from infection of BALB/c neonates with Rhesus rotavirus (RRV). RESULTS Liver Tregs from BA mice were decreased in number, activation marker expression, and suppressive function. Adoptive transfer studies revealed that RRV-infected mice that received Tregs had significantly increased survival (84%) compared to controls (12.5%). In addition, ablation of Tregs in older mice, followed by RRV infection, resulted in increased bile duct injury. CONCLUSIONS These studies demonstrate that dysregulation of Tregs is present in murine BA and that diminished Treg function may be implicated in the pathogenesis of human BA.
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Affiliation(s)
| | | | | | - Cara L. Mack
- University of Colorado, Denver,Children’s Hospital Colorado, Denver, CO 80262
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13
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Iwaya Y, Kobayashi M, Momose M, Hiraoka N, Sakai Y, Akamatsu T, Tanaka E, Ohtani H, Fukuda M, Nakayama J. High levels of FOXP3⁺ regulatory T cells in gastric MALT lymphoma predict responsiveness to Helicobacter pylori eradication. Helicobacter 2013; 18:356-62. [PMID: 23551894 DOI: 10.1111/hel.12051] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Although Helicobacter pylori eradication is a first-line treatment of gastric MALT lymphoma, roughly 25% of patients do not respond to treatment. CD4⁺ FOXP3⁺ regulatory T (Treg) cells regulate immune responses in physiological conditions and various inflammatory conditions, including H. pylori-associated diseases. Our goal was to determine how Treg cells affect responsiveness to H. pylori eradication therapy. MATERIALS AND METHODS We performed dual immunohistochemistry for CD4 and FOXP3 to evaluate the prevalence of FOXP3⁺ Treg cells in the stomach of 63 patients with MALT lymphoma and 55 patients with chronic active gastritis. Receiver operating characteristic analysis was carried out to determine the best cut-off point in differentiating H. pylori eradication responders from nonresponders. RESULTS Both the FOXP3⁺/CD4⁺ cell ratio and the absolute number of FOXP3⁺ cells per high-power field in MALT lymphoma were significantly greater in H. pylori eradication responders compared with nonresponders, suggesting that Treg cells function in regression mechanisms of MALT lymphomas. Cut-off points with good sensitivities and specificities were obtained to predict eradication outcome. CONCLUSIONS A high number of Treg cells or a high ratio of Treg cells to the total number of CD4⁺ T cells in gastric MALT lymphoma could predict responsiveness to eradication therapy.
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Affiliation(s)
- Yugo Iwaya
- Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan
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14
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Karlsson F, Martinez NE, Gray L, Zhang S, Tsunoda I, Grisham MB. Therapeutic evaluation of ex vivo-generated versus natural regulatory T-cells in a mouse model of chronic gut inflammation. Inflamm Bowel Dis 2013; 19:2282-2294. [PMID: 23893082 PMCID: PMC3812251 DOI: 10.1097/mib.0b013e31829c32dd] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The objectives of this study were to (a) evaluate and compare the ability of ex vivo-generated induced regulatory T cells (iTregs) and freshly isolated natural Tregs (nTregs) to reverse/attenuate preexisting intestinal inflammation in a mouse model of chronic colitis and (b) quantify the Treg-targeted gene expression profiles of these two Treg populations. We found that ex vivo-generated iTregs were significantly more potent than nTregs at attenuating preexisting colitis. This superior therapeutic activity was associated with increased accumulation of iTregs within the mesenteric lymph nodes and large and significant reductions in interleukin (IL)-6 and IL-17A expression in the colons of iTreg- versus nTreg-treated mice. The enhanced immunosuppressive activity of iTregs was not because of increased expression or stability of Foxp3 as iTregs and nTregs obtained from the mesenteric lymph nodes, and colons of reconstituted mice expressed similar levels of this important transcription factor. In addition, we observed a total of 27 genes that were either upregulated or downregulated in iTregs when compared with nTregs. Although iTregs were found to be superior at reversing established disease, their message levels of IL-10 and IL-35 and surface expression of the gut-homing molecules CCR9 and α4β7 were significantly reduced when compared with nTregs. Taken together, our data demonstrate that ex vivo-generated iTregs are significantly more potent than nTregs at attenuating preexisting gut inflammation despite reduced expression of classical regulatory cytokines and gut-homing molecules. Our data suggest that the immunosuppressive activity of iTregs may be because of their ability to directly or indirectly decrease expression of IL-6 and IL-17A within the inflamed bowel.
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Affiliation(s)
- Fridrik Karlsson
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
| | - Nicholas E. Martinez
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
| | - Laura Gray
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
| | - Songlin Zhang
- Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
| | - Ikuo Tsunoda
- Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana
| | - Matthew B. Grisham
- Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, Texas
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McCaskey SJ, Rondini EA, Clinthorne JF, Langohr IM, Gardner EM, Fenton JI. Increased presence of effector lymphocytes during Helicobacter hepaticus-induced colitis. World J Gastroenterol 2012; 18:1459-69. [PMID: 22509077 PMCID: PMC3319941 DOI: 10.3748/wjg.v18.i13.1459] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Revised: 11/12/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify and characterize drosophila mothers against decapentaplegic (SMAD)3-dependent changes in immune cell populations following infection with Helicobacter hepaticus (H. hepaticus).
METHODS: SMAD3-/- (n = 19) and colitis-resistant SMAD3+/- (n = 24) mice (8-10 wk of age) were infected with H. hepaticus and changes in immune cell populations [T lymphocytes, natural killer (NK) cells, T regulatory cells] were measured in the spleen and mesenteric lymph nodes (MsLNs) at 0 d, 3 d, 7 d and 28 d post-infection using flow cytometry. Genotype-dependent changes in T lymphocytes and granzyme B+ cells were also assessed after 28 d in proximal colon tissue using immunohistochemistry.
RESULTS: As previously observed, SMAD3-/-, but not SMAD3+/- mice, developed colitis, peaking at 4 wk post-infection. No significant changes in T cell subsets were observed in the spleen or in the MsLNs between genotypes at any time point. However, CD4+ and CD8+/CD62Llo cells, an effector T lymphocyte population, as well as NK cells (NKp46/DX5+) were significantly higher in the MsLNs of SMAD3-/- mice at 7 d and 28 d post-infection. In the colon, a higher number of CD3+ cells were present in SMAD3-/- compared to SMAD3+/– mice at baseline, which did not significantly change during infection. However, the number of granzyme B+ cells, a marker of cytolytic lymphocytes, significantly increased in SMAD3-/- mice 28 d post-infection compared to both SMAD3+/- mice and to baseline values. This was consistent with more severe colitis development in these animals.
CONCLUSION: Data suggest that defects in SMAD3 signaling increase susceptibility to H. hepaticus-induced colitis through aberrant activation and/or dysregulation of effector lymphocytes.
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16
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Dynamics and functions of CD4+CD25high regulatory T lymphocytes in Chinese rhesus macaques during the early stage of infection with SIVmac239. Arch Virol 2012; 157:961-7. [DOI: 10.1007/s00705-012-1252-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Accepted: 01/11/2012] [Indexed: 11/26/2022]
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18
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Maganto-García E, Tarrio ML, Grabie N, Bu DX, Lichtman AH. Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia. Circulation 2011; 124:185-95. [PMID: 21690490 PMCID: PMC3145407 DOI: 10.1161/circulationaha.110.006411] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Accepted: 05/11/2011] [Indexed: 12/31/2022]
Abstract
BACKGROUND Regulatory T cells (Treg) are present in atherosclerotic lesions and can modulate disease. In this study we characterized changes in Treg responses associated with prolonged hypercholesterolemia and lesion progression. METHODS AND RESULTS Low-density lipoprotein receptor null mice in which Treg express green fluorescent protein were fed a control or cholesterol-rich diet, and green fluorescent protein-positive cells were enumerated in lymphoid tissues and in aorta. Splenic Treg numbers increased after 4, 8, and 20 weeks in cholesterol-diet-fed mice. However, the number of circulating and lesional Treg peaked at 4 weeks and decreased significantly at 8 and 20 weeks, concomitant with increased numbers of CD4(+) effector T cells and increased lesion size over this period. Treg expression of selectin ligands and their ability to bind to aortic endothelium decreased after prolonged hypercholesterolemia, and apoptosis of lesional Treg increased. After 4 weeks of cholesterol-rich diet, a switch to a control diet for 4 weeks reduced serum cholesterol and stopped lesion growth, and the high aortic Treg content was maintained, compared with mice fed a cholesterol diet for 8 weeks. After the diet reversal, the splenic Treg retained the phenotype of Treg after 4 weeks of cholesterol diet. CONCLUSIONS Prolonged hypercholesterolemia impairs Treg but not effector T cell accumulation in lesions, but reversal of hypercholesterolemia can prevent loss of lesional Treg. Therefore, cholesterol-lowering therapies may induce dynamic and beneficial changes in Treg:effector T cell ratios in atherosclerotic lesions.
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MESH Headings
- Animals
- Atherosclerosis/blood
- Atherosclerosis/immunology
- Atherosclerosis/therapy
- CD4 Lymphocyte Count
- Cholesterol/adverse effects
- Cholesterol/blood
- Cholesterol/pharmacology
- Cholesterol, Dietary/adverse effects
- Cholesterol, Dietary/blood
- Cholesterol, Dietary/pharmacology
- Diet, Atherogenic
- Endothelium, Vascular/metabolism
- Hypercholesterolemia/blood
- Hypercholesterolemia/genetics
- Hypercholesterolemia/immunology
- Hypercholesterolemia/therapy
- Mice
- Mice, Knockout
- Receptors, LDL/genetics
- Receptors, LDL/metabolism
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
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Affiliation(s)
- Elena Maganto-García
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB 7, Boston, MA 02115, USA
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19
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Ohmichi Y, Hirakawa J, Imai Y, Fukuda M, Kawashima H. Essential role of peripheral node addressin in lymphocyte homing to nasal-associated lymphoid tissues and allergic immune responses. J Exp Med 2011; 208:1015-25. [PMID: 21518796 PMCID: PMC3092357 DOI: 10.1084/jem.20101786] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2010] [Accepted: 03/22/2011] [Indexed: 12/17/2022] Open
Abstract
Nasal-associated lymphoid tissue (NALT) is a mucosal immune tissue that provides immune responses against inhaled antigens. Lymphocyte homing to NALT is mediated by specific interactions between lymphocytes and high endothelial venules (HEVs) in NALT. In contrast to HEVs in other mucosal lymphoid tissues, NALT HEVs strongly express peripheral node addressins (PNAds) that bear sulfated glycans recognized by the monoclonal antibody MECA-79. We investigated the role of PNAd in lymphocyte homing to NALT using sulfotransferase N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST) 1 and GlcNAc6ST-2 double knockout (DKO) mice. The expression of PNAd in NALT HEVs was eliminated in DKO mice. Short-term homing assays indicated that lymphocyte homing to NALT was diminished by 90% in DKO mice. Production of antigen-specific IgE and the number of sneezes in response to nasally administered ovalbumin were also substantially diminished. Consistently, the NALT of DKO mice showed reduced production of IL-4 and increased production of IL-10 together with an increase in CD4(+)CD25(+) regulatory T cells (T(reg) cells). Compared with the homing of CD4(+)CD25(-) conventional T cells, the homing of CD4(+)CD25(+) T(reg) cells to NALT was less dependent on the L-selectin-PNAd interaction but was partially dependent on PSGL-1 (P-selectin glycoprotein ligand 1) and CD44. These results demonstrate that PNAd is essential for lymphocyte homing to NALT and nasal allergic responses.
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Affiliation(s)
- Yukari Ohmichi
- Laboratory of Microbiology and Immunology and the Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Jotaro Hirakawa
- Laboratory of Microbiology and Immunology and the Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Yasuyuki Imai
- Laboratory of Microbiology and Immunology and the Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
| | - Minoru Fukuda
- Glycobiology Unit, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037
| | - Hiroto Kawashima
- Laboratory of Microbiology and Immunology and the Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan
- PRESTO, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
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20
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Abstract
Forkhead box P3 (FOXP3)(+) regulatory T (T(Reg)) cells prevent autoimmune disease, maintain immune homeostasis and modulate immune responses during infection. To accomplish these tasks, T(Reg) cell activity is precisely controlled, and this requires T(Reg) cells to alter their migratory, functional and homeostatic properties in response to specific cues in the immune environment. We review progress in understanding the diversity of T(Reg) cells, T(Reg) cell function in different anatomical and inflammatory settings, and the influence of the immune environment on T(Reg) cell activity. We also consider how these factors affect immune-mediated disease in the contexts of infection, autoimmunity, cancer and transplantation.
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Affiliation(s)
- Daniel J Campbell
- Immunology Program, Benaroya Research Institute, Seattle, Washington 98103, USA.
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21
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Mailloux AW, Young MRI. Regulatory T-cell trafficking: from thymic development to tumor-induced immune suppression. Crit Rev Immunol 2010; 30:435-47. [PMID: 21083525 DOI: 10.1615/critrevimmunol.v30.i5.30] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Regulatory T cells (Tregs) have become a priority for many investigators in immunology due to their potent immunosuppressive and tolerogenic effects. While Treg activity is required for normal immune homeostasis, dysregulation of their numbers can induce autoimmunity or aid in the pathogenesis of disease. Therefore, great effort has been made to understand the mechanisms by which Tregs accumulate in different areas of the body. Like other lymphocytes, Tregs migrate in response to a network of chemotactic stimuli involving chemokines, chemokine receptors, integrins, and their corresponding ligands. However, many of these stimuli are exclusive to Tregs, inducing their migration while leaving conventional populations unaffected. It is these selective stimuli that result in increased ratios of Tregs among conventional effector populations, leading to changes in immune suppression and homeostasis. This review explores selective Treg trafficking during thymic Treg development, migration to secondary lymphoid tissues and emigration into the periphery during homeostatic conditions, inflammation, and the tumor microenvironment, placing emphasis on stimuli that selectively recruits Tregs to target locations.
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Affiliation(s)
- Adam W Mailloux
- Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
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22
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Nessi V, Nava S, Ruocco C, Toscani C, Mantegazza R, Antozzi C, Baggi F. Naturally occurring CD4+CD25+ regulatory T cells prevent but do not improve experimental myasthenia gravis. THE JOURNAL OF IMMUNOLOGY 2010; 185:5656-67. [PMID: 20881192 DOI: 10.4049/jimmunol.0903183] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
In the current study, we investigated whether naturally occurring CD4(+)CD25(+) T cells, separated by immunomagnetic anti-CD4 and anti-CD25 Abs from naive animals, are able to protect from experimental autoimmune myasthenia gravis (EAMG) and modify the progression of ongoing disease when administered to Torpedo californica acetylcholine receptor (AChR)-immunized Lewis rats. Even though CD4(+)CD25(+) and CD4(+)CD25(high) T cell frequencies were similar in the spleens and lymph nodes of EAMG and healthy rats, we observed that CD4(+)CD25(+) T cells isolated from the spleens of naive animals inhibited in vitro the Ag-induced proliferation of T cell lines specific to the self-peptide 97-116 of the anti-AChR subunit (R97-116), an immunodominant and myasthenogenic T cell epitope, whereas CD4(+)CD25(+) T cells purified from the spleens of EAMG rats were less effective. CD4(+)CD25(+) T cells from EAMG rats expressed less forkhead box transcription factor P3 but more CTLA-4 mRNA than healthy rats. Naive CD4(+)CD25(+) T cells, obtained from naive rats and administered to T. californica AChR-immunized animals according to a preventive schedule of treatment, reduced the severity of EAMG, whereas their administration 4 wk postinduction of the disease, corresponding to the onset of clinical symptoms (therapeutic treatment), was not effective. We think that the exogenous administration of CD4(+)CD25(+) naive T cells prevents the early events underlying the induction of EAMG, events linked to the T cell compartment (Ag recognition, epitope spreading, and T cell expansion), but fails to ameliorate ongoing EAMG, when the IgG-mediated complement attack to the AChR at the neuromuscular junction has already taken place.
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Affiliation(s)
- Valeria Nessi
- Neurology IV, Neurological Institute Foundation Carlo Besta, Milan, Italy
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23
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Makis A, Shipway D, Hatzimichael E, Galanakis E, Pshezhetskiy D, Chaliasos N, Stebbing J, Siamopoulou A. Cytokine and Adhesion Molecule Expression Evolves Between the Neutrophilic and Lymphocytic Phases of Viral Meningitis. J Interferon Cytokine Res 2010; 30:661-5. [DOI: 10.1089/jir.2009.0113] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Alexandros Makis
- Child Health Department, University of Ioannina Medical School, Ioannina, Greece
| | - David Shipway
- Department of Medical Oncology, Imperial College School of Medicine, Charing Cross Hospital, London, United Kingdom
| | | | | | - Dmitry Pshezhetskiy
- Department of Medical Oncology, Imperial College School of Medicine, Charing Cross Hospital, London, United Kingdom
| | - Nikolaos Chaliasos
- Child Health Department, University of Ioannina Medical School, Ioannina, Greece
| | - Justin Stebbing
- Department of Medical Oncology, Imperial College School of Medicine, Charing Cross Hospital, London, United Kingdom
| | - Antigone Siamopoulou
- Child Health Department, University of Ioannina Medical School, Ioannina, Greece
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24
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Woodworth HL, McCaskey SJ, Duriancik DM, Clinthorne JF, Langohr IM, Gardner EM, Fenton JI. Dietary Fish Oil Alters T Lymphocyte Cell Populations and Exacerbates Disease in a Mouse Model of Inflammatory Colitis. Cancer Res 2010; 70:7960-9. [DOI: 10.1158/0008-5472.can-10-1396] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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25
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Karlsson MR, Johansen FE, Kahu H, Macpherson A, Brandtzaeg P. Hypersensitivity and oral tolerance in the absence of a secretory immune system. Allergy 2010; 65:561-70. [PMID: 19886928 DOI: 10.1111/j.1398-9995.2009.02225.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Mucosal immunity protects the epithelial barrier by immune exclusion of foreign antigens and by anti-inflammatory tolerance mechanisms, but there is a continuing debate about the role of secretory immunoglobulins (SIgs), particularly SIgA, in the protection against allergy and other inflammatory diseases. Lack of secretory antibodies may cause immune dysfunction and affect mucosally induced (oral) tolerance against food antigens. METHODS We used polymeric Ig receptor (pIgR) knockout (KO) mice, which cannot export SIgA or SIgM, to study oral tolerance induction by ovalbumin (OVA) feeding and for parenteral antigen sensitization in the same animal. RESULTS Remarkable systemic hyperreactivity was observed in pIgR KO mice, as 50% died after intradermal OVA challenge, which was not seen in similarly sensitized and challenged wild-type (WT) mice. Oral tolerance induced by OVA completely protected the sensitized pIgR KO mice against anaphylaxis and suppressed antibody levels (particularly IgG1) as well as delayed-type hypersensitivity (DTH) to OVA. Delayed-type hypersensitivity to a bystander antigen, human serum albumin, was also suppressed and T-cell proliferation against OVA in vitro was reduced in tolerized compared with non-tolerized pIgR KO mice. This effect was largely mediated by CD25+ T cells. Adoptive transfer of splenic putative regulatory T cells (CD4+ CD25+) obtained from OVA-fed pIgR KO mice to naïve WT mice mediated suppression of DTH against OVA after sensitization of the recipients. CONCLUSION Compensatory regulatory T-cell function becomes critical in pIgR-deficient mice to avoid the potentially catastrophic effects of systemic immune hyperreactivity, presumably resulting from defective secretory antibody-mediated immune exclusion of microbial components.
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Affiliation(s)
- M R Karlsson
- Centre for Immune Regulation, Oslo University Hospital, University of Oslo, Rikshospitalet, Norway
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26
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Tartar DM, VanMorlan AM, Wan X, Guloglu FB, Jain R, Haymaker CL, Ellis JS, Hoeman CM, Cascio JA, Dhakal M, Oukka M, Zaghouani H. FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 184:3377-85. [PMID: 20181889 PMCID: PMC2843758 DOI: 10.4049/jimmunol.0903324] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Recently, traces of double-positive FoxP3(+)RORgammat(+) T cells were identified and viewed as dual programming differentiation intermediates geared toward development into T regulatory or Th17 cells. In this study, we report that FoxP3(+)RORgammat(+) intermediates arise in the NOD mouse T cell repertoire prior to inflammation and can be expanded with tolerogen without further differentiation. Furthermore, FoxP3(+)RORgammat(+) cells express both CD62L and membrane-bound TGFbeta and use the former to traffic to the pancreas and the latter to suppress effector T cells both in vitro and in vivo. The cells perform these functions as FoxP3(+)RORgammat(+) intermediates, despite being able to terminally differentiate into either FoxP3(+)RORgammat(-) T regulatory or FoxP3(-)RORgammat(+) Th17 cells on polarization. These previously unrecognized observations extend plasticity to both differentiation and function and indicate that the intermediates are poised to traffic to sites of inflammation and target diverse pathogenic T cells, likely without prior conditioning by effector T cells, thus broadening efficacy against autoimmunity.
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MESH Headings
- Animals
- Cell Differentiation/immunology
- Cell Separation
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Flow Cytometry
- Forkhead Transcription Factors/immunology
- Forkhead Transcription Factors/metabolism
- Interleukin-17/immunology
- Interleukin-17/metabolism
- Lymphocyte Activation/immunology
- Mice
- Mice, Inbred NOD
- Nuclear Receptor Subfamily 1, Group F, Member 3/immunology
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- T-Lymphocyte Subsets/cytology
- T-Lymphocyte Subsets/immunology
- T-Lymphocyte Subsets/metabolism
- T-Lymphocytes, Helper-Inducer/cytology
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
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Affiliation(s)
- Danielle M. Tartar
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Amie M. VanMorlan
- Department of Child Health., University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Xiaoxiao Wan
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - F. Betul Guloglu
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Renu Jain
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Cara L. Haymaker
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Jason S. Ellis
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Christine M. Hoeman
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Jason A. Cascio
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mermagya Dhakal
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Mohamed Oukka
- Center for Neurologic Diseases Harvard University, Boston, MA, 02115, USA
| | - Habib Zaghouani
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
- Department of Child Health., University of Missouri School of Medicine, Columbia, MO, 65212, USA
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Alpha-1,2-mannosidase and hence N-glycosylation are required for regulatory T cell migration and allograft tolerance in mice. PLoS One 2010; 5:e8894. [PMID: 20126660 PMCID: PMC2811199 DOI: 10.1371/journal.pone.0008894] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Accepted: 12/11/2009] [Indexed: 11/19/2022] Open
Abstract
Background Specific immunological unresponsiveness to alloantigens can be induced in vivo by treating mice with a donor alloantigen in combination with a non-depleting anti-CD4 antibody. This tolerance induction protocol enriches for alloantigen reactive regulatory T cells (Treg). We previously demonstrated that alpha-1,2-mannosidase, an enzyme involved in the synthesis and processing of N-linked glycoproteins, is highly expressed in tolerant mice, in both graft infiltrating leukocytes and peripheral blood lymphocytes. Principal Findings In this study we have identified that alpha-1,2-mannosidase expression increases in CD25+CD4+ Treg when they encounter alloantigen in vivo. When alpha-1,2-mannosidase enzyme activity was blocked, Treg retained their capacity to suppress T cell proliferation in vitro but were unable to bind to physiologically relevant ligands in vitro. Further in vivo analysis demonstrated that blocking alpha-1,2-mannosidase in Treg resulted in the migration of significantly lower numbers to the peripheral lymph nodes in skin grafted mice following adoptive transfer, where they were less able to inhibit the proliferation of naïve T cells responding to donor alloantigen and hence unable prevent allograft rejection in vivo. Significance Taken together, our results suggest that activation of alloantigen reactive Treg results in increased alpha-1,2-mannosidase expression and altered N-glycosylation of cell surface proteins. In our experimental system, altered N-glycosylation is not essential for intrinsic Treg suppressive capacity, but is essential in vivo as it facilitates Treg migration to sites where they can regulate immune priming. Migration of Treg is central to their role in regulating in vivo immune responses and may require specific changes in N-glycosylation upon antigen encounter.
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L-selectin: role in regulating homeostasis and cutaneous inflammation. J Dermatol Sci 2009; 56:141-7. [PMID: 19889515 DOI: 10.1016/j.jdermsci.2009.10.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2009] [Revised: 10/01/2009] [Accepted: 10/02/2009] [Indexed: 01/07/2023]
Abstract
The maintenance of immune surveillance and the generation of normal immune responses are dependent on leukocyte migration to appropriate lymphoid and non-lymphoid tissues. The process of leukocyte migration occurs through complex and highly regulated interactions between the circulating leukocytes and the vascular endothelium. Multiple families of adhesion molecules as well as specific chemoattractants and their cognate receptors function to stabilize these interactions and induce migration into the tissue. L-selectin is a key adhesion molecule that regulates both the migration of leukocytes at sites of inflammation and the recirculation of lymphocytes between blood and lymphoid tissues. L-selectin-mediated lymphocyte recirculation is required for maintaining the appropriate tissue distribution of lymphocyte subpopulations including naïve and effector subsets such as regulatory T cells. In addition, L-selectin-mediated entry into peripheral lymph nodes is required for optimal induction of lymphocyte homeostatic proliferation during lymphopenia. Importantly, L-selectin has been shown to have both adhesive and signaling functions during leukocyte migration. Specifically, L-selectin is highly efficient at capturing free-flowing leukocytes from the blood and supporting subsequent fast rolling interactions along the vascular endothelium. During rolling, synergistic interactions between L-selectin and integrin functions slow leukocyte rolling velocities allowing for chemoattractant-induced activation and eventual firm adhesion of the leukocyte to the vascular endothelium. Engagement of L-selectin by ligand generates transmembrane signals leading to activation of intracellular signaling pathways, increased integrin binding affinity, and enhanced chemotaxis. L-selectin has also been shown to mediate leukocyte recruitment during chronic inflammatory and autoimmune diseases and thus is a potential therapeutic target for drug development.
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Yessoufou A, Plé A, Moutairou K, Hichami A, Khan NA. Docosahexaenoic acid reduces suppressive and migratory functions of CD4+CD25+ regulatory T-cells. J Lipid Res 2009; 50:2377-88. [PMID: 19561360 DOI: 10.1194/jlr.m900101-jlr200] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Immunological tolerance is one of the fundamental aspects of the immune system. The CD4(+)CD25(+) regulatory T (Treg) cells have emerged as key players in the development of tolerance to self and foreign antigens. However, little is known about the endogenous factors and mechanisms controlling their suppressive capacity on immune response. In this study, we observed that docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, diminished, in a dose-dependent manner, the capacity of Treg cells to inhibit the CD4(+)CD25(-) effector T-cell proliferation. DHA not only reduced the migration of Treg cells toward chemokines but also downregulated the mRNA expression of CCR-4 and CXCR-4 in Treg cells. DHA also curtailed ERK1/2 and Akt phosphorylation and downregulated the Smad7 levels in these cells. Contradictorily, DHA upregulated the mRNA expression of Foxp3, CTLA-4, TGF-beta, and IL-10; nonetheless, this fatty acid increased the expression of p27(KIP1) mRNA, known to be involved in Treg cell unresponsiveness. In Foxp3-immunoprepitated nuclear proteins, DHA upregulated histone desacetylase 7 levels that would again participate in the unresposnsiveness of these cells. Finally, a DHA-enriched diet also diminished, ex vivo, the suppressive capacity of Treg cells. Altogether, these results suggest that DHA, by diminishing Treg cell functions, may play a key role in health and disease.
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Affiliation(s)
- Akadiri Yessoufou
- University of Burgundy, Unité Propre de Recherche de l'Enseignement Supérieur, Lipids and Cell Signaling, Faculty of Life Sciences, Dijon, France
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Sobel DO, Ahvazi B, Amjad F, Mitnaul L, Pontzer C. Interferon-tau inhibits the development of diabetes in NOD mice. Autoimmunity 2009; 41:543-53. [PMID: 18608174 DOI: 10.1080/08916930802194195] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Interferon-alpha (IFN-alpha) inhibits the development of diabetes in animal models of autoimmune diabetes. However, the mechanism of the action is not fully understood and drug toxicity could limit its potential clinical utility. Interferon-tau (IFN-tau) is another type 1 interferon, which has less toxicity but may have different biologic activity than IFN-alpha. This study explores the effect of IFN-tau on the diabetic process in non-obese diabetic (NOD) mice. IFN-tau by intraperitoneal, subcutaneous, or oral routes of administration decreased the development of spontaneous diabetes in NOD mice. Islet inflammation was decreased 50%. IFN-tau administration to recipient mice prevented the development of passively transferred and cyclophosphamide accelerated diabetes. IFN-tau treatment also decreased anti-islet effector activity of NOD splenic cells. Immunoregulatory activity of splenic cells was augmented by IFN-tau administration as was the number of splenic CD25+CD4+ cells. Concanavalin A (Con A)-induced release of IFN-gamma was decreased in spleen cells from IFN-tau treated mice. In conclusion, IFN-tau inhibits spontaneous autoimmune diabetes and passively transferred diabetes in the NOD mouse. This diabetes sparing activity may be due to an induction of regulatory cells, possibly CD25+CD4+ T cells, which in turn inhibit anti-islet effector cell activity and the development of insulitis and diabetes. Due to the lower drug toxicity, IFN-tau could be a better drug candidate than IFN-alpha for experimental clinical trials.
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Affiliation(s)
- Douglas O Sobel
- Georgetown University Children's Medical Center, NW Washington, DC 20007, USA.
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31
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Hebeda CB, Teixeira SA, Muscará MN, Vinolo MAR, Curi R, Mello SBVD, Farsky SHP. In vivo blockade of Ca(+2)-dependent nitric oxide synthases impairs expressions of L-selectin and PECAM-1. Biochem Biophys Res Commun 2008; 377:694-698. [PMID: 18948084 DOI: 10.1016/j.bbrc.2008.10.055] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2008] [Accepted: 10/09/2008] [Indexed: 01/17/2023]
Abstract
Interactions of leukocytes with endothelium play a role for the immune system modulated by endogenous agents, such as glucocorticoids and nitric oxide (NO). Glucocorticoids inhibit leukocyte-endothelial interactions whereas the role of NO is still controversial. In this study, the activity of Ca(+2)-dependent nitric oxide synthases was in vivo blocked in male Wistar rats by given l-NAME, 20mgkg(-1) for 14 days dissolved in drinking water and expression of adhesion molecules involved in leukocyte-endothelial interactions was investigated. Expressions of L-selectin and PECAM-1 in peripheral leukocytes and PECAM-1 in endothelial cells were reduced by l-NAME treatment. Only L-selectin expression was controlled at transcriptional levels. These effects were not dependent on endogenous glucocorticoids, as corticosterone levels were not altered in l-NAME-treated rats. Our results show that NO, produced at physiological levels, controls expression of constitutive adhesion molecules expressions in cell membranes by different mechanisms of action.
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Affiliation(s)
- Cristina B Hebeda
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 0550-900, Av Prof. Lineu Prestes 580-BI13 B, SP, Brazil
| | - Simone A Teixeira
- Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Marcelo N Muscará
- Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Marco Antonio R Vinolo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Rui Curi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Suzana B V de Mello
- Rheumatology Division, Department of Internal Medicine, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil
| | - Sandra H P Farsky
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 0550-900, Av Prof. Lineu Prestes 580-BI13 B, SP, Brazil.
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32
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Li H, Guo Z, Jiang X, Zhu H, Li X, Mao N. Mesenchymal stem cells alter migratory property of T and dendritic cells to delay the development of murine lethal acute graft-versus-host disease. Stem Cells 2008; 26:2531-41. [PMID: 18635870 DOI: 10.1634/stemcells.2008-0146] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Due to the potent immunoregulatory capacity, mesenchymal stem cells (MSCs) have been used in clinical trials to treat acute graft-versus-host disease (aGvHD), although the detailed in vivo mechanisms remain elusive. In a murine lethal aGvHD model, MSCs delayed the development of the disease. Interestingly, we found that MSC infusion increased the number of T lymphocytes in the secondary lymphoid organs (SLOs). Since the expression of CD62L and CCR7 is prerequisite for lymphocyte migration into SLOs, the in vitro experiments revealed that in the presence of MSCs, T lymphocytes (including CD4(+)CD25(+) regulatory T cells) preferred to take the naive-like phenotype (CD62L(+)/CCR7(+)) in mixed lymphocyte reaction and maintained the migratory activity elicited by secondary lymphoid tissue chemokine (SLC). Dendritic cells (DCs) are the initiator of immune response. CCR7 expression is pivotal for their maturation and migration into SLOs. However, CCR7 expression and SLC-driven migratory activity of DCs were remarkably suppressed by MSC coculture. The processes above were realized mainly through secretory mechanism. Consistently, MSC infusion maintained T lymphocytes to take CD62L(+)/CCR7(+) phenotype and decreased the CCR7 expression and proportion of DCs in SLOs of aGvHD mice. In conclusion, the altered migratory properties of T cells and DCs might contribute to the immunosuppressive activity of transplanted MSCs in the setting of aGvHD. Disclosure of potential conflicts of interest is found at the end of this article.
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Affiliation(s)
- Hong Li
- Department of Cell Biology, Institute of Basic Medical Sciences, Beijing, China.
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Komura K. [Ultraviolet: a regulator of immunity]. NIHON RINSHO MEN'EKI GAKKAI KAISHI = JAPANESE JOURNAL OF CLINICAL IMMUNOLOGY 2008; 31:125-131. [PMID: 18587222 DOI: 10.2177/jsci.31.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Humans establish acquired immune systems during the growth, which can sufficiently eliminate pathogen avoiding immune responses to self, such as allergy and autoimmunity. An imbalance of the acquired immune system leads up to immune-mediated disorders. Ultraviolet (UV) exposure helps to establish the normal peripheral tolerance to contact allergen avoiding excessive immune responses. By contrast, UV develops kinds of autoimmune diseases on rare occasions, suggesting that abnormality in the process of UV-induced peripheral tolerance may induce these diseases. To elucidate the mechanism of UV-induced tolerance is possible to provide a new approach for the management of immune diseases. In the current review, focus is on the suggested players of UV-induced tolerance, blocking mechanisms on the elicitation phase of contact hypersensitivity, and the association between UV and autoimmunity. The major impact in basic immunology in this area is the discovery of cell surface marker of regulatory T cells. Therefore, we first discuss about the association of regulatory/suppressor T cells with UV-induced tolerance. Since the elicitation phase depends on cellular influx into the inflammatory sites, which is tightly regulated by adhesion molecules, we also focused on the role of adhesion molecules. Finally, this paper also includes statistical findings concerning the association between UV-radiation and the prevalence of a myositis specific autoantibody. Thus, UV is one of the nice regulators of an immune network and the knowledge of UV-mediated immune regulation will be translated into new therapeutic strategies to human immune-mediated disorders.
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Affiliation(s)
- Kazuhiro Komura
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Kodera M, Grailer JJ, Karalewitz APA, Subramanian H, Steeber DA. T lymphocyte migration to lymph nodes is maintained during homeostatic proliferation. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2008; 14:211-224. [PMID: 18312727 DOI: 10.1017/s1431927608080215] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
The immune system maintains appropriate cell numbers through regulation of cell proliferation and death. Normal tissue distribution of lymphocytes is maintained through expression of specific adhesion molecules and chemokine receptors such as L-selectin and CCR7, respectively. Lymphocyte insufficiency or lymphopenia induces homeostatic proliferation of existing lymphocytes to increase cell numbers. Interestingly, homeostatic proliferation of T lymphocytes induces a phenotypic change from naïve- to memory-type cell. Naïve T cells recirculate between blood and lymphoid tissues whereas memory T cells migrate to nonlymphoid sites such as skin and gut. To assess effects of homeostatic proliferation on migratory ability of T cells, a murine model of lymphopenia-induced homeostatic proliferation was used. Carboxyfluorescein diacetate, succinimidyl ester-labeled wild-type splenocytes were adoptively transferred into recombination activation gene-1-deficient mice and analyzed by flow cytometry, in vitro chemotactic and in vivo migration assays, and immunofluorescence microscopy. Homeostatically proliferated T cells acquired a mixed memory-type CD44high L-selectinhigh CCR7low phenotype. Consistent with this, chemotaxis to secondary lymphoid tissue chemokine in vitro was reduced by 22%-34%. By contrast, no differences were found for migration or entry into lymph nodes during in vivo migration assays. Therefore, T lymphocytes that have undergone homeostatic proliferation recirculate using mechanisms similar to naïve T cells.
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Affiliation(s)
- Masanari Kodera
- Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA
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Sinclair LV, Finlay D, Feijoo C, Cornish GH, Gray A, Ager A, Okkenhaug K, Hagenbeek TJ, Spits H, Cantrell DA. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol 2008; 9:513-21. [PMID: 18391955 PMCID: PMC2857321 DOI: 10.1038/ni.1603] [Citation(s) in RCA: 319] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2007] [Accepted: 03/04/2008] [Indexed: 01/22/2023]
Abstract
Phosphatidylinositol-3-OH kinase (PI(3)K) and the nutrient sensor mTOR are evolutionarily conserved regulators of cell metabolism. Here we show that PI(3)K and mTOR determined the repertoire of adhesion and chemokine receptors expressed by T lymphocytes. The key lymph node-homing receptors CD62L (L-selectin) and CCR7 were highly expressed on naive T lymphocytes but were downregulated after immune activation. CD62L downregulation occurred through ectodomain proteolysis and suppression of gene transcription. The p110delta subunit of PI(3)K controlled CD62L proteolysis through mitogen-activated protein kinases, whereas control of CD62L transcription by p110delta was mediated by mTOR through regulation of the transcription factor KLF2. PI(3)K-mTOR nutrient-sensing pathways also determined expression of the chemokine receptor CCR7 and regulated lymphocyte trafficking in vivo. Hence, lymphocytes use PI(3)K and mTOR to match metabolism and trafficking.
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Affiliation(s)
- Linda V Sinclair
- Department of Cell Biology and Immunology, University of Dundee, DD1 5EH, UK
| | - David Finlay
- Department of Cell Biology and Immunology, University of Dundee, DD1 5EH, UK
| | - Carmen Feijoo
- Department of Cell Biology and Immunology, University of Dundee, DD1 5EH, UK
| | - Georgina H Cornish
- Immune Cell Biology, The National Institute for Medical Research, London, NW7 1AA, UK
| | - Alex Gray
- Division of Molecular Physiology, University of Dundee, DD1 5EH, UK
| | - Ann Ager
- Department of Medical Biochemistry and Immunology, Cardiff University, CF14 4XN, UK
| | - Klaus Okkenhaug
- Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, CB2 4AT, UK
| | - Thijs J Hagenbeek
- Department of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Department of Immunology Discovery, Genentech Inc., South San Francisco, California CA 94080, USA
| | - Hergen Spits
- Department of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Department of Immunology Discovery, Genentech Inc., South San Francisco, California CA 94080, USA
| | - Doreen A Cantrell
- Department of Cell Biology and Immunology, University of Dundee, DD1 5EH, UK
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Mahnke K, Bedke T, Enk AH. Regulatory conversation between antigen presenting cells and regulatory T cells enhance immune suppression. Cell Immunol 2008; 250:1-13. [PMID: 18313653 DOI: 10.1016/j.cellimm.2008.01.004] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2007] [Revised: 01/16/2008] [Accepted: 01/17/2008] [Indexed: 01/07/2023]
Abstract
Regulatory T cells (Treg) were originally described by their suppressive function exerted on effector T cells, but recent evidence also reveals interactions with antigen presenting cells (APCs). In general, all major subpopulations of APCs, i.e., dendritic cells (DC), B cells and monocytes/macrophages (Mvarphi), respond to exposure to Treg by down regulation of their antigen presenting function, upregulation of immunosuppressive molecules and secretion of immunosuppressive cytokines. Thus, Treg gain influence on the innate immune system and are able to augment their immunosuppressive capacities by blocking the effective priming of T effector cells by APCs. Conversely, APCs have an important role in nurturing peripheral Treg populations, since it has been shown that immature DC, as well as alternatively activated Mvarphi, are able to induce Treg de novo. These properties are dependent on the expression of surface molecules (CTLA-4, F4/80) and the production of soluble factors such as IL-10 and Indoleamine 2,3-dioxygenase by the APC subpopulations. On the whole, the mutual interaction of Treg and APCs enables Treg to sustain their immunosuppressive functions which, in healthy individuals, may be crucial for the maintenance of peripheral tolerance.
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Affiliation(s)
- Karsten Mahnke
- Department of Dermatology, University Hospital Heidelberg, Vosstrasse 11, D-69115 Heidelberg, Germany.
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Ho J, Kurtz CC, Naganuma M, Ernst PB, Cominelli F, Rivera-Nieves J. A CD8+/CD103high T cell subset regulates TNF-mediated chronic murine ileitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 180:2573-80. [PMID: 18250468 PMCID: PMC3036968 DOI: 10.4049/jimmunol.180.4.2573] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recruitment of lymphocytes to sites of inflammation requires the sequential engagement of adhesion molecules and chemokine receptors. Of these, the lectin-like molecule CD44 has been particularly implicated in inflammatory trafficking. Using a TNF-driven model of chronic ileitis (i.e., B6.129P-Tnf(Delta)(ARE) mice) that recapitulates many features of Crohn's disease, we demonstrate dynamic changes in the expression and functional state of CD44 on CD8+ T cells. These cells coexpress CD44 and L-selectin, giving them a surface phenotype similar to that of central memory T cells. Yet functionally they exhibit the phenotype of effector T cells, because they produce IFN-gamma. Unexpectedly, depletion of the CD8+ population had no effect on the severity of ileitis. Further analyses showed a second CD8+ population that lacked CD44, but expressed CD103, produced TGF-beta, inhibited the proliferation of CD4+ in vitro, and attenuated adoptively transferred ileitis in vivo, most likely counteracting the proinflammatory role of the CD44(high) subset. Collectively, these data suggest that the presence or absence of CD44 and CD103 on the CD8+ lymphocyte surface defines functionally distinct subsets of CD8+ T cells in vivo. These inflammation-driven populations exert distinct roles during the development of chronic ileitis, and influence the balance of effector and regulatory functions in the chronically inflamed small intestine.
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Affiliation(s)
- Johnson Ho
- Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908
| | - Courtney C. Kurtz
- Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908
| | - Makoto Naganuma
- Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908
| | - Peter B. Ernst
- Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908
| | - Fabio Cominelli
- Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908
| | - Jesús Rivera-Nieves
- Digestive Health Center of Excellence, University of Virginia Health Sciences Center, Charlottesville, VA 22908
- Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, CO 80206
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Redistribution of FOXP3-Positive Regulatory T Cells From Lymphoid Tissues to Peripheral Blood in HIV-Infected Patients. J Acquir Immune Defic Syndr 2007; 27:673-8. [DOI: 10.1097/qai.0b013e31815b69ae] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Saito S, Shima T, Nakashima A, Shiozaki A, Ito M, Sasaki Y. What is the role of regulatory T cells in the success of implantation and early pregnancy? J Assist Reprod Genet 2007; 24:379-86. [PMID: 17668314 PMCID: PMC3454956 DOI: 10.1007/s10815-007-9140-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PROBLEM The immune system is well controlled by the balance between immunostimulation and immunoregulation. CD4(+)CD25(+) regulatory T (Treg) cells and an enzyme called indoleamine-2, 3-dioxygenase (IDO) mediate maternal tolerance of the allogeneic fetus. Treg cells, therefore, may prevent early pregnancy loss due to maternal 'rejection.' METHODS The latest understanding of tolerance during pregnancy is reviewed. RESULTS AND CONCLUSIONS Recent data show that CD4(+)CD25(+) Treg cells play essential roles in the induction and maintenance of tolerance, and that they augment the IDO activity in dendritic cells and macrophages. Therefore, CD4(+)CD25(+) Treg cells and IDO enzyme may cooperate in the induction of tolerance during pregnancy. Treg deficiency is associated with very early post-implantation loss and spontaneous abortion in animal models, and low Treg levels are associated with recurrent miscarriages in humans.
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Affiliation(s)
- Shigeru Saito
- Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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40
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Ueha S, Yoneyama H, Hontsu S, Kurachi M, Kitabatake M, Abe J, Yoshie O, Shibayama S, Sugiyama T, Matsushima K. CCR7 mediates the migration of Foxp3+ regulatory T cells to the paracortical areas of peripheral lymph nodes through high endothelial venules. J Leukoc Biol 2007; 82:1230-8. [PMID: 17698914 DOI: 10.1189/jlb.0906574] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Thymus-derived forkhead box p3(+) naturally occurring regulatory T cells (nTreg) are thought to circulate throughout the body to maintain peripheral immunological self-tolerance through interactions with dendritic cells (DCs), resulting in regulation of conventional T cells. However, the chemokine receptors, which are putatively involved in the in vivo migration of nTreg, have not been fully established. Here, we demonstrated that lymph node nTreg preferentially migrated to the paracortical area of lymph nodes after adoptive transfer, where they were observed to make contact frequently with CD8alpha(+) DCs and CD8alpha(-) CD11b(-) DCs. This migration of nTreg to the paracortical areas was impaired severely when cells were prepared from CCR7-deficient mice. However, to some extent, CCR7-independent migration of nTreg in such CCR7-deficient mice was also observed, but this occurred mainly in the medullary high endothelial venules. Taken together, these data provide the evidence that CCR7 mediates nTreg migration to the paracortical areas of lymph nodes under steady-state conditions; however, CCR7-independent migration also takes place in the medulla.
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MESH Headings
- Adoptive Transfer
- Air
- Animals
- Cell Movement
- Cell Proliferation
- Chemotaxis
- Dendritic Cells/cytology
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Endothelium, Lymphatic/cytology
- Endothelium, Lymphatic/metabolism
- Flow Cytometry
- Fluorescent Antibody Technique
- Forkhead Transcription Factors/immunology
- Forkhead Transcription Factors/metabolism
- Gene Expression Regulation
- Kinetics
- Lymph Nodes
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, Antigen, T-Cell/metabolism
- Receptors, CCR4/antagonists & inhibitors
- Receptors, CCR4/metabolism
- Receptors, CCR7/genetics
- Receptors, CCR7/physiology
- Receptors, Chemokine/metabolism
- T-Lymphocytes, Regulatory/cytology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Venules/cytology
- Venules/metabolism
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Affiliation(s)
- Satoshi Ueha
- Department of Molecular Preventive Medicine and SORST, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Tokyo, Japan
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Saito S, Shiozaki A, Sasaki Y, Nakashima A, Shima T, Ito M. Regulatory T cells and regulatory natural killer (NK) cells play important roles in feto-maternal tolerance. Semin Immunopathol 2007; 29:115-22. [PMID: 17621697 DOI: 10.1007/s00281-007-0067-2] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
In the early pregnancy decidua, lymphocytes express some activation markers on their surface, suggesting that maternal lymphocytes are activated and recognize the semiallograftic fetus. Therefore, the immunoregulation system must work to prevent fetus rejection. Recent data showed that parts of the immunoregulation system such as CD4+CD25+ regulatory T (Treg) cells, Th3 cells, Tr1 cells, regulatory NK cells, and a tryptophan-catabolizing enzyme, indolamine 2,3 deoxygenase, play very important roles in the maintenance of pregnancy. Not only Treg cells but also regulatory NK cells may inhibit maternal T cell or NK cell fetal attack.
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Affiliation(s)
- Shigeru Saito
- Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
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