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Dabbaghipour R, Ahmadi E, Entezam M, Farzam OR, Sohrabi S, Jamali S, Sichani AS, Paydar H, Baradaran B. Concise review: The heterogenous roles of BATF3 in cancer oncogenesis and dendritic cells and T cells differentiation and function considering the importance of BATF3-dependent dendritic cells. Immunogenetics 2024; 76:75-91. [PMID: 38358555 DOI: 10.1007/s00251-024-01335-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/23/2023] [Indexed: 02/16/2024]
Abstract
The transcription factor, known as basic leucine zipper ATF-like 3 (BATF3), is a crucial contributor to the development of conventional type 1 dendritic cells (cDC1), which is definitely required for priming CD8 + T cell-mediated immunity against intracellular pathogens and malignancies. In this respect, BATF3-dependent cDC1 can bring about immunological tolerance, an autoimmune response, graft immunity, and defense against infectious agents such as viruses, microbes, parasites, and fungi. Moreover, the important function of cDC1 in stimulating CD8 + T cells creates an excellent opportunity to develop a highly effective target for vaccination against intracellular pathogens and diseases. BATF3 has been clarified to control the development of CD8α+ and CD103+ DCs. The presence of BATF3-dependent cDC1 in the tumor microenvironment (TME) reinforces immunosurveillance and improves immunotherapy approaches, which can be beneficial for cancer immunotherapy. Additionally, BATF3 acts as a transcriptional inhibitor of Treg development by decreasing the expression of the transcription factor FOXP3. However, when overexpressed in CD8 + T cells, it can enhance their survival and facilitate their transition to a memory state. BATF3 induces Th9 cell differentiation by binding to the IL-9 promoter through a BATF3/IRF4 complex. One of the latest research findings is the oncogenic function of BATF3, which has been approved and illustrated in several biological processes of proliferation and invasion.
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Affiliation(s)
- Reza Dabbaghipour
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Ahmadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mona Entezam
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Rahbar Farzam
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Sohrabi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sajjad Jamali
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Saber Sichani
- Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Hadi Paydar
- Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Guo WW, Su XH, Wang MY, Han MZ, Feng XM, Jiang EL. Regulatory T Cells in GVHD Therapy. Front Immunol 2021; 12:697854. [PMID: 34220860 PMCID: PMC8250864 DOI: 10.3389/fimmu.2021.697854] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/02/2021] [Indexed: 12/25/2022] Open
Abstract
Graft versus host disease (GVHD) is a common complication and the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Pharmacological immunosuppression used in GVHD prophylaxis and treatment lacks specificity and can increase the likelihood of infection and relapse. Regulatory T lymphocytes (Tregs) play a vital role in restraining excessive immune responses and inducing peripheral immune tolerance. In particular, clinical trials have demonstrated that Tregs can prevent and treat GVHD, without increasing the risk of relapse and infection. Hence, adoptive transfer of Tregs to control GVHD using their immunosuppressive properties represents a promising therapeutic approach. To optimally apply Tregs for control of GVHD, a thorough understanding of their biology is necessary. In this review, we describe the biological characteristics of Tregs, including how the stability of FOXP3 expression can be maintained. We will also discuss the mechanisms underlying Tregs-mediated modulation of GVHD and approaches to effectively increase Tregs’ numbers. Finally, we will examine the developing trends in the use of Tregs for clinical therapy.
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Affiliation(s)
- Wen-Wen Guo
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Xiu-Hua Su
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ming-Yang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Ming-Zhe Han
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Xiao-Ming Feng
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Er-Lie Jiang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
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STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function. Cell Mol Immunol 2021; 18:632-643. [PMID: 33500563 PMCID: PMC8027033 DOI: 10.1038/s41423-020-00611-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 11/26/2020] [Indexed: 01/30/2023] Open
Abstract
Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor- and self-DNA-elicited antitumor immunity and autoimmunity. However, STING can also suppress tumor immunity and autoimmunity. STING signaling in host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Host hematopoietic antigen-presenting cells (APCs) play key roles in donor T-cell priming during GVHD initiation. However, how STING regulates host hematopoietic APCs after allo-HCT remains unknown. We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs. STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT. Using bone marrow chimeras, we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease. Furthermore, STING on host CD11c+ cells played a dominant role in suppressing allogeneic T-cell responses. Mechanistically, STING deficiency resulted in increased survival, activation, and function of APCs, including macrophages and dendritic cells. Consistently, constitutive activation of STING attenuated the survival, activation, and function of APCs isolated from STING V154M knock-in mice. STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression, and migration into intestinal tissues, resulting in accelerated/exacerbated GVHD. Using pharmacologic approaches, we demonstrated that systemic administration of a STING agonist (bis-(3'-5')-cyclic dimeric guanosine monophosphate) to recipient mice before transplantation significantly reduced GVHD mortality. In conclusion, we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.
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Molina MS, Stokes J, Hoffman EA, Eremija J, Zeng Y, Simpson RJ, Katsanis E. Bendamustine Conditioning Skews Murine Host DCs Toward Pre-cDC1s and Reduces GvHD Independently of Batf3. Front Immunol 2020; 11:1410. [PMID: 32765499 PMCID: PMC7378358 DOI: 10.3389/fimmu.2020.01410] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 06/02/2020] [Indexed: 11/21/2022] Open
Abstract
Graft-versus-host disease (GvHD) remains the second leading cause of death in allogeneic hematopoietic stem cell transplantation recipients, highlighting the need for improved preventative strategies. Our laboratory has previously demonstrated in an experimental bone marrow transplantation (BMT) model that bendamustine combined with total body irradiation (BEN+TBI) is a safer alternative to cyclophosphamide with TBI (CY+TBI). The biological mechanisms of action of BEN have not been fully elucidated and likely involve multiple cell populations. Host dendritic cells (DCs) can prime naïve donor T-cells immediately following transplantation, making host DCs critical for the initiation phase of GvHD. We hypothesized that BEN+TBI conditioning favorably alters host DC composition to reduce GvHD. We demonstrate that host DCs treated with BEN+TBI induce less allogeneic T-cell proliferation than those conditioned with CY+TBI. We further show that BEN+TBI conditioning results in greater total numbers of all host DC subsets but with a more favorable composition compared to CY+TBI with significantly larger proportions of type 1 conventional DCs (cDC1), a highly regulatory DC subset capable of suppressing GvHD. Our studies using recipient Batf3 KO mice indicate that CD8α+ cDC1s are largely dispensable for the reduced GvHD following BEN+TBI conditioning. We found a higher frequency of host pre-cDC1s with BEN+TBI conditioning in both wild-type (WT) and Batf3 KO mice, which was inversely associated with GvHD. Additionally, we observed that BEN treatment results in greater expression of Flt3 receptor (CD135) on host DCs compared to CY, potentially contributing to the skewing of host DCs toward cDC1s. Further, BEN+TBI conditioning results in host cDCs with greater expression of PIR-B, an inhibitory receptor capable of preventing lethal GvHD. We conclude that BEN+TBI is a safer alternative to CY+TBI, resulting in a greater frequency of host pre-cDC1s and limiting GvHD.
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Affiliation(s)
- Megan S. Molina
- Department of Immunobiology, University of Arizona, Tucson, AZ, United States
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
| | - Jessica Stokes
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
| | - Emely A. Hoffman
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
| | - Jelena Eremija
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
| | - Yi Zeng
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
- Department of Pathology, University of Arizona, Tucson, AZ, United States
| | - Richard J. Simpson
- Department of Immunobiology, University of Arizona, Tucson, AZ, United States
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
- Department of Nutritional Science, University of Arizona, Tucson, AZ, United States
| | - Emmanuel Katsanis
- Department of Immunobiology, University of Arizona, Tucson, AZ, United States
- Department of Pediatrics, University of Arizona, Tucson, AZ, United States
- Department of Pathology, University of Arizona, Tucson, AZ, United States
- University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States
- Department of Medicine, University of Arizona, Tucson, AZ, United States
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5
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The primacy of gastrointestinal tract antigen-presenting cells in lethal graft-versus-host disease. Blood 2020; 134:2139-2148. [PMID: 31697827 DOI: 10.1182/blood.2019000823] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/24/2019] [Indexed: 12/26/2022] Open
Abstract
Allogeneic stem cell transplantation is a cornerstone of curative therapy for high-risk and/or advanced hematological malignancies but remains limited by graft-versus-host disease (GVHD). GVHD is initiated by the interaction between recipient antigen-presenting cells (APCs) and donor T cells, culminating in T-cell differentiation along pathogenic type-1 and type-17 paradigms at the expense of tolerogenic regulatory T-cell patterns. Type-1 and type-17 T cells secrete cytokines (eg, granulocyte-macrophage colony-stimulating factor and interferon-γ) critical to the cytokine storm that amplifies expansion of donor APCs and their alloantigen presentation. It has become increasingly clear that pathogenic donor T-cell differentiation is initiated by both professional recipient APCs (eg, dendritic cells [DCs]) and nonprofessional APCs (eg, epithelial and mesenchymal cells), particularly within the gastrointestinal (GI) tract. In the immediate peritransplantation period, these APCs are profoundly modified by pathogen-associated molecular pattern (PAMP)/damage-associated molecular pattern (DAMP) signals derived from conditioning and intestinal microbiota. Subsequently, donor DCs in the GI tract are activated by DAMP/PAMP signals in the colon that gain access to the lamina propria once the mucosal barrier mucosa is compromised by GVHD. This results in donor DC expansion and alloantigen presentation in the colon and subsequent migration into the mesenteric lymph nodes. Here, new donor T cells are primed, expanded, differentiated, and imprinted with gut-homing integrins permissive of migration into the damaged GI tract, resulting in the lethal feed-forward cascade of GVHD. These new insights into our understanding of the cellular and molecular factors initiating GVHD, both spatially and temporally, give rise to a number of logical therapeutic targets, focusing on the inhibition of APC function in the GI tract.
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6
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Zhang X, Arnold IC, Müller A. Mechanisms of persistence, innate immune activation and immunomodulation by the gastric pathogen Helicobacter pylori. Curr Opin Microbiol 2020; 54:1-10. [PMID: 32007716 DOI: 10.1016/j.mib.2020.01.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 01/03/2020] [Indexed: 12/20/2022]
Abstract
The gastric bacterium Helicobacter pylori efficiently evades innate immune detection and persistently colonizes its human host. Understanding the genetic determinants that H. pylori uses to establish and maintain persistence, along with their cellular targets, is key to our understanding of the pathogenesis of this extraordinarily successful bacterial colonizer of the human stomach. This review highlights recent advances in elucidating innate immune recognition of H. pylori, its interactions with myeloid cells and the consequences that this very local infection has for immune responses at extragastric sites in models of allergy, autoimmunity and parasitic infection. The human-specific, gram-negative gastric colonizer and carcinogen H. pylori represents the prototype of a persistent bacterial pathogen. It is transmitted during early childhood, typically from mother to infant, and is believed to persist in its human host from the cradle to the grave. The tremendous success of H. pylori in infecting and colonizing half of the world's population, and in continuously accompanying humans since they migrated out of Africa over 60000 years ago, can largely be attributed to its ability to manipulate the host immune system to its own advantage, and to thereby ensure its own persistence and chronicity. In his final years as an active PI, Stanley Falkow increasingly recognized the need to understand bacterial persistence strategies as a prerequisite of understanding the pathogenesis of chronic bacterial infections, and, inspired in large part by Denise Monack's work on Salmonella persistence, many of our discussions at the time revolved around this topic. Multiple labs have since made important contributions to our understanding of innate immune detection of H. pylori, the types and polarization of adaptive immune responses that ensue, the ability of H. pylori to skew such immune responses to its advantage, and its ability to manipulate the host immune system with far-reaching, even systemic consequences. This review attempts to cover some of these topics, with a particular focus on the most recent contributions by researchers in the field.
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Affiliation(s)
- Xiaozhou Zhang
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Isabelle C Arnold
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
| | - Anne Müller
- Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
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7
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BATF3-dependent dendritic cells drive both effector and regulatory T-cell responses in bacterially infected tissues. PLoS Pathog 2019; 15:e1007866. [PMID: 31188899 PMCID: PMC6590837 DOI: 10.1371/journal.ppat.1007866] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 06/24/2019] [Accepted: 05/23/2019] [Indexed: 12/23/2022] Open
Abstract
The gastric lamina propria of mice that have been experimentally infected with the pathobiont Helicobacter pylori hosts a dense network of myeloid cells that includes BATF3-dependent CD103+ dendritic cells (DCs). We show here that CD103+ DCs are strictly required for gastric Th1 responses to H. pylori and for H. pylori infection control. A similar dependence of type 1 immunity on CD103+ DCs is observed in a Mycobacterium bovis BCG infection model, and in a syngeneic colon cancer model. Strikingly, we find that not only the expansion and/or recruitment of Th1 cells, but also of peripherally induced, neuropilin-negative regulatory T-cells to sites of infection requires BATF3-dependent DCs. A shared feature of the examined models is the strongly reduced production of the chemokines and CXCR3 ligands CXCL9, 10 and 11 in BATF3-deficient mice. The results implicate BATF3-dependent DCs in the recruitment of CXCR3+ effector and regulatory T-cells to target tissues and in their local expansion. In this work, Arnold & Zhang et al report that CD103+ DCs are required for protective Th1 responses, infection control of mucosal and systemic bacterial pathogens, and anti-tumor immunity driven by CD4+ Th1 cells and CD8+ T cells. CD103+ DCs further specifically promote the recruitment of Tbet+ peripherally induced Tregs to sites of infection. The results implicate CD103+ DCs in the trafficking of CXCR3+ Tbet+ T-cells to sites of infection and tumorigenesis.
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8
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Yu H, Tian Y, Wang Y, Mineishi S, Zhang Y. Dendritic Cell Regulation of Graft-Vs.-Host Disease: Immunostimulation and Tolerance. Front Immunol 2019; 10:93. [PMID: 30774630 PMCID: PMC6367268 DOI: 10.3389/fimmu.2019.00093] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/14/2019] [Indexed: 12/12/2022] Open
Abstract
Graft-vs.-host disease (GVHD) remains a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Significant progresses have been made in defining the dichotomous role of dendritic cells (DCs) in the development of GVHD. Host-derived DCs are important to elicit allogeneic T cell responses, whereas certain donor-types of DCs derived from newly engrafted hematopoietic stem/progenitor cells (HSPCs) can amply this graft-vs.-host reaction. In contrast, some DCs also play non-redundant roles in mediating immune tolerance. They induce apoptotic deletion of host-reactive donor T cells while promoting expansion and function of regulatory T cells (Treg). Unfortunately, this tolerogenic effect of DCs is impaired during GVHD. Severe GVHD in patients subject to allo-HSCT is associated with significantly decreased number of circulating peripheral blood DCs during engraftment. Existing studies reveal that GVHD causes delayed reconstitution of donor DCs from engrafted HSPCs, impairs the antigen presentation function of newly generated DCs and reduces the capacity of DCs to regulate Treg. The present review will discuss the importance of DCs in alloimmunity and the mechanism underlying DC reconstitution after allo-HSCT.
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Affiliation(s)
- Hongshuang Yu
- Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, United States
| | - Yuanyuan Tian
- Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, United States
| | - Ying Wang
- Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, United States
| | - Shin Mineishi
- Department of Medicine, Pennsylvania State University, Hershey, PA, United States
| | - Yi Zhang
- Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, United States,Department of Microbiology & Immunology, Temple University, Philadelphia, PA, United States,*Correspondence: Yi Zhang
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9
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TIGIT-Fc alleviates acute graft-versus-host disease by suppressing CTL activation via promoting the generation of immunoregulatory dendritic cells. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3085-3098. [PMID: 29960041 DOI: 10.1016/j.bbadis.2018.06.022] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 06/25/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
Abstract
Graft-versus-host disease (GVHD) is the most common complication and major limitation of allogeneic hematopoietic stem cell transplantation. The CD226/TIGIT-CD155 signal is critical for the cross-talk between T cells and dendritic cells (DCs). Studies have shown that blockade of the CD226-CD155 interaction, using an anti-CD226 antibody, can significantly ameliorate GVHD. It has also been reported that a TIGIT-Fc fusion protein exerts immunosuppressive effects by binding to CD155 on DCs. Here, we used a mouse allogeneic acute GVHD model to explore the therapeutic potential and mechanism of action of TIGIT-Fc. C57/BL6 and Balb/c mice were used as hematopoietic cell graft donors and recipients, respectively. In the TIGIT-Fc-treated mice, GVHD symptom occurrence and mortality were delayed compared to that in isotype control group mice. Histopathological analyses revealed that following TIGIT-Fc treatment, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. The percentage of CD8+IFN-γ+ and CD8+ granzyme B+ cells significantly decreased in the TIGIT-Fc group. Moreover, treatment with TIGIT-Fc, even after the onset of GVHD, ameliorated symptoms and prolonged survival. TIGIT-Fc also inhibited CD8+ T cell activation in vitro; this was dependent on the presence of CD155 on bone marrow-derived dendritic cells (BMDCs) and on IL-10 production. In addition, TIGIT-CD155 ligation triggered both Erk phosphorylation and STAT3 nuclear translocation. These data indicate that TIGIT plays an important role in the development of GVHD and is an ideal molecular target to treat acute GVHD.
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10
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Moutuou MM, Pagé G, Zaid I, Lesage S, Guimond M. Restoring T Cell Homeostasis After Allogeneic Stem Cell Transplantation; Principal Limitations and Future Challenges. Front Immunol 2018; 9:1237. [PMID: 29967605 PMCID: PMC6015883 DOI: 10.3389/fimmu.2018.01237] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/17/2018] [Indexed: 11/29/2022] Open
Abstract
For several leukemia patients, allogeneic stem cell transplantation (allogeneic-SCT) is the unique therapeutic modality that could potentially cure their disease. Despite significant progress made in clinical management of allogeneic-SCT, acute graft-versus-host disease (aGVHD) and infectious complications remain the second and third cause of death after disease recurrence. Clinical options to restore immunocompetence after allogeneic-SCT are very limited as studies have raised awareness about the safety with regards to graft-versus-host disease (GVHD). Preclinical works are now focusing on strategies to improve thymic functions and to restore the peripheral niche that have been damaged by alloreactive T cells. In this mini review, we will provide a brief overview about the adverse effects of GVHD on the thymus and the peripheral niche and the resulting negative outcome on peripheral T cell homeostasis. Finally, we will discuss the potential relevance of coordinating our studies on thymic rejuvenation and improvement of the peripheral lymphoid niche to achieve optimal T cell regeneration in GVHD patients.
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Affiliation(s)
- Moutuaata M Moutuou
- Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université of Montréal, Montréal, QC, Canada
| | - Gabriel Pagé
- Département de Microbiologie, Infectiologie et Immunologie, Université of Montréal, Montréal, QC, Canada
| | - Intesar Zaid
- Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université of Montréal, Montréal, QC, Canada
| | - Sylvie Lesage
- Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université of Montréal, Montréal, QC, Canada
| | - Martin Guimond
- Division d'Hématologie-Oncologie, Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université of Montréal, Montréal, QC, Canada
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11
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Mohammadpour H, O'Neil R, Qiu J, McCarthy PL, Repasky EA, Cao X. Blockade of Host β2-Adrenergic Receptor Enhances Graft-versus-Tumor Effect through Modulating APCs. THE JOURNAL OF IMMUNOLOGY 2018; 200:2479-2488. [PMID: 29445008 DOI: 10.4049/jimmunol.1701752] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 01/24/2018] [Indexed: 11/19/2022]
Abstract
Allogeneic hematopoietic cell transplantation is a potential curative therapy for hematologic malignancies. Host APCs are pivotal to the desired graft-versus-tumor (GVT) effect. Recent studies have shown that β2-adrenergic receptor (β2AR) signaling can have an important impact on immune cell function, including dendritic cells (DCs). In this article, we demonstrate that pretreatment of host mice with a β2AR blocker significantly increases the GVT effect of donor CD8+ T cells by decreasing tumor burden without increasing graft-versus-host disease. β2AR-deficient host mice have significantly increased effector memory and central memory CD8+ T cells and improved reconstitution of T cells, including CD4+Foxp3+ regulatory T cells. Notably, β2AR deficiency induces increased CD11c+ DC development. Also, β2AR-deficient bone marrow-derived DCs induce higher CD8+ T cell proliferation and improved tumor killing in vitro. Metabolic profiling shows that β2AR deficiency renders DCs more immunogenic through upregulation of mTOR activity and reduction of STAT3 phosphorylation. Altogether, these findings demonstrate an important role for host β2AR signaling in suppressing T cell reconstitution and GVT activity.
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Affiliation(s)
- Hemn Mohammadpour
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263
| | - Rachel O'Neil
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263.,Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201
| | - Jingxin Qiu
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; and
| | - Philip L McCarthy
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263
| | - Elizabeth A Repasky
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263
| | - Xuefang Cao
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263; .,Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201
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12
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Perkey E, Maillard I. New Insights into Graft-Versus-Host Disease and Graft Rejection. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2017; 13:219-245. [PMID: 29099650 DOI: 10.1146/annurev-pathol-020117-043720] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Allogeneic transplantation of foreign organs or tissues has lifesaving potential, but can lead to serious complications. After solid organ transplantation, immune-mediated rejection mandates the use of prolonged global immunosuppression and limits the life span of transplanted allografts. After bone marrow transplantation, donor-derived immune cells can trigger life-threatening graft-versus-host disease. T cells are central mediators of alloimmune complications and the target of most existing therapeutic interventions. We review recent progress in identifying multiple cell types in addition to T cells and new molecular pathways that regulate pathogenic alloreactivity. Key discoveries include the cellular subsets that function as potential sources of alloantigens, the cross talk of innate lymphoid cells with damaged epithelia and with the recipient microbiome, the impact of the alarmin interleukin-33 on alloreactivity, and the role of Notch ligands expressed by fibroblastic stromal cells in alloimmunity. While refining our understanding of transplantation immunobiology, these findings identify new therapeutic targets and new areas of investigation.
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Affiliation(s)
- Eric Perkey
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA;
| | - Ivan Maillard
- Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA; .,Department of Internal Medicine, Division of Hematology-Oncology, and Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.,Department of Medicine, Division of Hematology-Oncology, and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
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Mavers M, Maas-Bauer K, Negrin RS. Invariant Natural Killer T Cells As Suppressors of Graft-versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 2017; 8:900. [PMID: 28824628 PMCID: PMC5534641 DOI: 10.3389/fimmu.2017.00900] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 07/13/2017] [Indexed: 11/30/2022] Open
Abstract
Invariant natural killer T (iNKT) cells serve as a bridge between innate and adaptive immunity and have been shown to play an important role in immune regulation, defense against pathogens, and cancer immunity. Recent data also suggest that this compartment of the immune system plays a significant role in reducing graft-versus-host disease (GVHD) in the setting of allogeneic hematopoietic stem cell transplantation. Murine studies have shown that boosting iNKT numbers through certain conditioning regimens or adoptive transfer leads to suppression of acute or chronic GVHD. Preclinical work reveals that iNKT cells exert their suppressive function by expanding regulatory T cells in vivo, though the exact mechanism by which this occurs has yet to be fully elucidated. Human studies have demonstrated that a higher number of iNKT cells in the graft or in the peripheral blood of the recipient post-transplantation are associated with a reduction in GVHD risk, importantly without a loss of graft-versus-tumor effect. In two separate analyses of many immune cell subsets in allogeneic grafts, iNKT cell dose was the only parameter associated with a significant improvement in GVHD or in GVHD-free progression-free survival. Failure to reconstitute iNKT cells following allogeneic transplantation has also been associated with an increased risk of relapse. These data demonstrate that iNKT cells hold promise for future clinical application in the prevention of GVHD in allogeneic stem cell transplantation and warrant further study of the immunoregulatory functions of iNKT cells in this setting.
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Affiliation(s)
- Melissa Mavers
- Divisions of Hematology/Oncology and Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, United States
| | - Kristina Maas-Bauer
- Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA, United States
| | - Robert S Negrin
- Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA, United States
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Bone marrow mesenchymal stem cells inhibit dendritic cells differentiation and maturation by microRNA-23b. Biosci Rep 2017; 37:BSR20160436. [PMID: 28096318 PMCID: PMC5398252 DOI: 10.1042/bsr20160436] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 12/23/2016] [Accepted: 01/17/2017] [Indexed: 12/20/2022] Open
Abstract
Research on regulation and its mechanism of bone marrow mesenchymal stem cells (BMSCs) on dendritic cells (DCs), which is the initiating factor in immune response has applicable clinical value. Although BMSCs have a significant regulatory effect on the maturation of DCs, its molecular mechanism is still unclear. BMSCs and DCs, were co-cultured by different concentration ratios. Flow cytometry was used to detect the expression of DC markers (CD83, CD11c). Quantitative reverse transcription PCR (qRT-PCR) was used to measure the expression of related genes in RNA level. Expression of the target proteins was detected with using Western blot assay. miRNA inhibitor and miRNA mimic were used to suppress and up-regulate the expression of the target gene. In this research, our results demonstrated that BMSCs notably inhibited maturation of DCs in the co-culture system of BMSCs and DCs and confirmed that this inhibition is due to overexpression of miR-23b. Furthermore, this research found that miR-23b overexpression inhibited the expression of p50/p65, thus blocked the activation of the NF-κB pathway. In conclusion, BMSCs affected the activation of NF-κB pathway through miR-23b overexpression resulting in inhibition of the maturation and differentiation of DCs.
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da Silva MB, da Cunha FF, Terra FF, Camara NOS. Old game, new players: Linking classical theories to new trends in transplant immunology. World J Transplant 2017; 7:1-25. [PMID: 28280691 PMCID: PMC5324024 DOI: 10.5500/wjt.v7.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 11/16/2016] [Accepted: 12/07/2016] [Indexed: 02/05/2023] Open
Abstract
The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.
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Batf3 selectively determines acquisition of CD8 + dendritic cell phenotype and function. Immunol Cell Biol 2016; 95:215-223. [PMID: 27897162 PMCID: PMC5309136 DOI: 10.1038/icb.2016.83] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/29/2016] [Accepted: 08/30/2016] [Indexed: 12/26/2022]
Abstract
Batf3 is a transcription factor that impacts the development of CD103+ tissue-resident dendritic cells (DCs). However, whether Batf3 is absolutely required for the development of CD8+ DCs remains controversial. Id2 is required for CD8+ DC development. Here we show that bone marrow chimeric mice with a deletion of Id2 in the CD11c compartment lose the ability to reject a skin graft expressing a non-self protein antigen or mount a delayed hypersensitivity response. In contrast, Batf3-/- mice remained competent for skin graft rejection and delayed hypersensitivity, and retained a CD8+ DC population with markers characteristic of the CD11b+ DC lineage, including CD11b, CD4 and CD172α, as well as the key regulator transcription factor IRF4, but lacked IRF8 expression. CD8+ DCs in Batf3-/- mice took up and cleaved protein antigen and larger particles but were unable to phagocytose dying cells, a characteristic feature to the CD8+ DC lineage. These data clarify a requirement for CD8+ lineage DCs to induce effectors of neo-antigen-driven skin graft rejection, and improve our understanding of DC subtype commitment by demonstrating that in the absence of Batf3 CD8+ DCs can change their fate and become CD11b+ DCs.
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Alloantigen presentation and graft-versus-host disease: fuel for the fire. Blood 2016; 127:2963-70. [PMID: 27030390 DOI: 10.1182/blood-2016-02-697250] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 03/05/2016] [Indexed: 12/16/2022] Open
Abstract
Allogeneic stem cell transplantation (SCT) is a unique procedure, primarily in patients with hematopoietic malignancies, involving chemoradiotherapy followed by the introduction of donor hematopoietic and immune cells into an inflamed and lymphopenic environment. Interruption of the process by which recipient alloantigen is presented to donor T cells to generate graft-versus-host disease (GVHD) represents an attractive therapeutic strategy to prevent morbidity and mortality after SCT and has been increasingly studied in the last 15 years. However, the immune activation resulting in GVHD has no physiological equivalent in nature; alloantigen is ubiquitous, persists indefinitely, and can be presented by multiple cell types at numerous sites, often on incompatible major histocompatibility complex, and occurs in the context of intense inflammation early after SCT. The recognition that alloantigen presentation is also critical to the development of immunological tolerance via both deletional and regulatory mechanisms further adds to this complexity. Finally, GVHD itself appears capable of inhibiting the presentation of microbiological antigens by donor dendritic cells late after SCT that is mandatory for the establishment of effective pathogen-specific immunity. Here, we review our current understanding of alloantigen, its presentation by various antigen-presenting cells, subsequent recognition by donor T cells, and the potential of therapeutic strategies interrupting this disease-initiating process to modify transplant outcome.
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Toubai T, Mathewson N, Oravecz-Wilson K, Reddy P. Host CD8α+ dendritic cells may be a key factor for separating graft-versus-host disease from graft-versus-leukemia. Biol Blood Marrow Transplant 2015; 21:775-6. [PMID: 25591846 DOI: 10.1016/j.bbmt.2015.01.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 01/08/2015] [Indexed: 02/02/2023]
Affiliation(s)
- Tomomi Toubai
- Blood and Marrow Transplantation Program, Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
| | - Nathan Mathewson
- Blood and Marrow Transplantation Program, Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
| | - Katherine Oravecz-Wilson
- Blood and Marrow Transplantation Program, Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
| | - Pavan Reddy
- Blood and Marrow Transplantation Program, Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
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