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de Castro YS, Nascimento LS, da Silva JA, da Conceição Souza R, Araújo GN, de Oliveira SC, Nahn Junior EP, Peixoto-Rangel AL. Increased CD8 dim and Decreased CD8 bright T Cells as Immunological Signature for Multibacilary Leprosy Patients. Immunology 2025. [PMID: 40325949 DOI: 10.1111/imm.13937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 04/06/2025] [Accepted: 04/17/2025] [Indexed: 05/07/2025] Open
Abstract
Leprosy, a chronic infectious disease caused by Mycobacterium leprae, manifests in a spectrum of clinical forms and severity. This study investigated the percentage of CD8+ T cells and their subpopulations (CD8bright and CD8dim T cells) in leprosy patients stratified by clinical forms, bacterial load, and age. No significant differences were observed in the overall percentage of CD8+ T cells among healthy controls and leprosy patients. However, an increased percentage of CD8dim T cells and a decreased percentage of CD8bright T cells were associated with severe multibacillary and lepromatous forms of leprosy, independent of bacillary load. Further, these cellular profiles correlated more strongly with disease severity than with age, in spite of elderly multibacillary patients exhibiting significant reductions in CD8bright T cells and increases in CD8dim T cells compared to young or middle-aged paucibacillary patients, but not compared to young and middle-aged multibacillary patients. These findings suggest that CD8bright and CD8dim T cell profiles are critical indicators of disease progression and severity in leprosy, highlighting their potential as biomarkers for clinical evaluation.
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Affiliation(s)
- Yuri Scheidegger de Castro
- Laboratório de Biologia Do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual Do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes City, Brazil
| | - Letícia Silva Nascimento
- Laboratório de Biologia Do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual Do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes City, Brazil
| | - Juliana Azevedo da Silva
- Laboratório de Biologia Do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual Do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes City, Brazil
| | - Rebeka da Conceição Souza
- Laboratório de Biologia Do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual Do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes City, Brazil
| | - Gabriel Nogueira Araújo
- Laboratório de Biologia Do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual Do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes City, Brazil
| | | | | | - Alba Lucínia Peixoto-Rangel
- Laboratório de Biologia Do Reconhecer, Centro de Biociências e Biotecnologia, Universidade Estadual Do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes City, Brazil
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Shum IO, Merkert S, Malysheva S, Jahn K, Lachmann N, Verboom M, Frieling H, Hallensleben M, Martin U. An Improved Protocol for Targeted Differentiation of Primed Human Induced Pluripotent Stem Cells into HLA-G-Expressing Trophoblasts to Enable the Modeling of Placenta-Related Disorders. Cells 2023; 12:2070. [PMID: 37626882 PMCID: PMC10453333 DOI: 10.3390/cells12162070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/27/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Abnormalities at any stage of trophoblast development may result in pregnancy-related complications. Many of these adverse outcomes are discovered later in pregnancy, but the underlying pathomechanisms are constituted during the first trimester. Acquiring developmentally relevant material to elucidate the disease mechanisms is difficult. Human pluripotent stem cell (hPSC) technology can provide a renewable source of relevant cells. BMP4, A83-01, and PD173074 (BAP) treatment drives trophoblast commitment of hPSCs toward syncytiotrophoblast (STB), but lacks extravillous trophoblast (EVT) cells. EVTs mediate key functions during placentation, remodeling of uterine spiral arteries, and maintenance of immunological tolerance. We optimized the protocol for a more efficient generation of HLA-Gpos EVT-like trophoblasts from primed hiPSCs. Increasing the concentrations of A83-01 and PD173074, while decreasing bulk cell density resulted in an increase in HLA-G of up to 71%. Gene expression profiling supports the advancements of our treatment regarding the generation of trophoblast cells. The reported differentiation protocol will allow for an on-demand access to human trophoblast cells enriched for HLA-Gpos EVT-like cells, allowing for the elucidation of placenta-related disorders and investigating the immunological tolerance toward the fetus, overcoming the difficulties in obtaining primary EVTs without the need for a complex differentiation pathway via naïve pluripotent or trophoblast stem cells.
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Affiliation(s)
- Ian O. Shum
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, 30625 Hannover, Germany
- REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
| | - Sylvia Merkert
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, 30625 Hannover, Germany
- REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, 30625 Hannover, Germany
| | - Svitlana Malysheva
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, 30625 Hannover, Germany
- REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
| | - Kirsten Jahn
- Laboratory of Molecular Neurosciences, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, 30625 Hannover, Germany
| | - Nico Lachmann
- REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, 30625 Hannover, Germany
- Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, 30625 Hannover, Germany
| | - Murielle Verboom
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany
| | - Helge Frieling
- Laboratory of Molecular Neurosciences, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, 30625 Hannover, Germany
| | - Michael Hallensleben
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, 30625 Hannover, Germany
| | - Ulrich Martin
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery (HTTG), Hannover Medical School, 30625 Hannover, Germany
- REBIRTH-Research Center for Translational and Regenerative Medicine, Hannover Medical School, 30625 Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, 30625 Hannover, Germany
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Maebele LT, Mulaudzi TV, Yasasve M, Dlamini Z, Damane BP. Immunomodulatory Gene-Splicing Dysregulation in Tumorigenesis: Unmasking the Complexity. Molecules 2023; 28:5984. [PMID: 37630236 PMCID: PMC10458946 DOI: 10.3390/molecules28165984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer is a global health concern with rising incidence, morbidity, and mortality. The interaction between the tumor and immune cells within the tumor microenvironment is facilitated by signaling pathways driven by immunomodulatory proteins. Alternative splicing regulates the production of multiple immunomodulatory proteins with diverse functionality from a single mRNA transcript. Splicing factors are pivotal in modulating alternative splicing processes but are also subject to regulation. The dysregulation of alternative splicing may result from splicing factor (SF) abnormal expression levels and mutations in the cis and trans-acting elements and small nuclear RNA (snRNA) molecules. Aberrant splicing may generate abnormal mRNA transcripts encoding isoforms with altered functions that contribute to tumorigenesis or cancer progression. This review uncovers the complexity of immunomodulatory genes splicing dysregulation in oncogenesis. Identifying specific immunomodulatory splicing isoforms that contribute to cancer could be utilized to improve current immunotherapeutic drugs or develop novel therapeutic interventions for cancer.
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Affiliation(s)
| | - Thanyani Victor Mulaudzi
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
| | - Madhavan Yasasve
- Department of Oral Medicine and Radiology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, India
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
| | - Botle Precious Damane
- Department of Surgery, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
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IL-10-producing memory B regulatory cells as a novel target for HLA-G to prolong human kidney allograft survival. Hum Immunol 2023:S0198-8859(23)00044-7. [PMID: 36934068 DOI: 10.1016/j.humimm.2023.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 03/18/2023]
Abstract
Despite the growing interest in the role of regulatory B cells (Bregs) in autoimmunity, their distinct role and function in kidney transplant outcomes remain elusive. Here, we retrospectively analyzed the proportion of Bregs, transitional Bregs (tBregs) and memory Bregs (mBregs) and their capacity to produce IL-10 in non-rejected (NR) versus rejected (RJ) kidney transplant recipients. In the NR group, we observed a significant increase in the proportion of mBregs (CD19+CD24hiCD27+) but no difference in tBregs (CD19+CD24hiCD38+), as compared to the RJ group. We also observed a significant increase in IL-10-producing mBregs (CD19+CD24hiCD27+IL-10+) in the NR group. As our group and others have previously reported a potential role of the human leukocyte antigen G (HLA-G) in human renal allograft survival, notably through IL-10, we then investigated possible crosstalk between HLA-G and IL-10+ mBregs. Our ex vivo data suggest a role of HLA-G in enhancing IL-10+ mBreg expansion upon stimulation, which further decreased CD3+ T cell proliferation capability. Using RNA-sequencing (RNA-seq), we identified potential key signaling pathways involved in HLA-G-driven IL-10+ mBreg expansion, such as the MAPK, TNF and chemokine signaling pathways. Together, our study highlights a novel HLA-G-mediated IL-10-producing mBreg pathway that may serve as a therapeutic target to improve kidney allograft survival.
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Zhang X, Wang X, Qin L, Lu X, Liu Z, Li Z, Yuan L, Wang R, Jin J, Ma Z, Wu H, Zhang Y, Zhang T, Su B. Changing roles of CD3 + CD8 low T cells in combating HIV-1 infection. Chin Med J (Engl) 2023; 136:433-445. [PMID: 36580634 PMCID: PMC10106209 DOI: 10.1097/cm9.0000000000002458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Cluster of differentiation 8 (CD8 T) cells play critical roles in eradicating human immunodeficiency virus (HIV)-1 infection, but little is known about the effects of T cells expressing CD8 at low levels (CD8 low ) or high levels (CD8 high ) on HIV-1 replication inhibition after HIV-1 invasion into individual. METHODS Nineteen patients who had been acutely infected with HIV-1 (AHI) and 20 patients with chronic infection (CHI) for ≥2 years were enrolled in this study to investigate the dynamics of the quantity, activation, and immune responses of CD3 + CD8 low T cells and their counterpart CD3 + CD8 high T cells at different stages of HIV-1 infection. RESULTS Compared with healthy donors, CD3 + CD8 low T cells expanded in HIV-1-infected individuals at different stages of infection. As HIV-1 infection progressed, CD3 + CD8 low T cells gradually decreased. Simultaneously, CD3 + CD8 high T cells was significantly reduced in the first month of AHI and then increased gradually as HIV-1 infection progressed. The classical activation of CD3 + CD8 low T cells was highest in the first month of AHI and then reduced as HIV-1 infection progressed and entered the chronic stage. Meanwhile, activated CD38 - HLA-DR + CD8 low T cells did not increase in the first month of AHI, and the number of these cells was inversely associated with viral load ( r = -0.664, P = 0.004) but positively associated with the CD4 T-cell count ( r = 0.586, P = 0.014). Increased programmed cell death protein 1 (PD-1) abundance on CD3 + CD8 low T cells was observed from the 1st month of AHI but did not continue to be enhanced, while a significant T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) abundance increase was observed in the 12th month of infection. Furthermore, increased PD-1 and TIGIT abundance on CD3 + CD8 low T cells was associated with a low CD4 T-cell count (PD-1: r = -0.456, P = 0.043; TIGIT: r = -0.488, P = 0.029) in CHI. Nonetheless, the nonincrease in PD-1 expression on classically activated CD3 + CD8 low T cells was inversely associated with HIV-1 viremia in the first month of AHI ( r = -0.578, P = 0.015). Notably, in the first month of AHI, few CD3 + CD8 low T cells, but comparable amounts of CD3 + CD8 high T cells, responded to Gag peptides. Then, weaker HIV-1-specific T-cell responses were induced in CD3 + CD8 low T cells than CD3 + CD8 high T cells at the 3rd and 12th months of AHI and in CHI. CONCLUSIONS Our findings suggest that CD3 + CD8 low T cells play an anti-HIV role in the first month of infection due to their abundance but induce a weak HIV-1-specific immune response. Subsequently, CD3 + CD8 low T-cell number decreased gradually as infection persisted, and their anti-HIV functions were inferior to those of CD3 + CD8 high T cells.
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Affiliation(s)
- Xin Zhang
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Xiuwen Wang
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Ling Qin
- Research Center for Biomedical Resources, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Xiaofan Lu
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Zhiying Liu
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Zhen Li
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Lin Yuan
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Rui Wang
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Junyan Jin
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Zhenglai Ma
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Hao Wu
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Yonghong Zhang
- Research Center for Biomedical Resources, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Tong Zhang
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Bin Su
- Beijing Key Laboratory for HIV/AIDS Research, Sino-French Joint Laboratory for Research on Humoral Immune Response to HIV Infection, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
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Le Floc’h B, Costet N, Vu N, Bernabeu-Gentey P, Pronier C, Houssel-Debry P, Boudjéma K, Renac V, Samson M, Amiot L. Involvement of circulating soluble HLA-G after liver transplantation in the low immunogenicity of hepatic allograft. PLoS One 2023; 18:e0282736. [PMID: 36897848 PMCID: PMC10004504 DOI: 10.1371/journal.pone.0282736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 02/20/2023] [Indexed: 03/11/2023] Open
Abstract
Graft rejection is a critical risk in solid-organ transplantation. To decrease such risk, an understanding of the factors involved in low immunogenicity of liver allografts could potentially make it possible to transfer this tolerogenic property to other transplanted organs. HLA-G, a natural physiological molecule belonging to the Human Leukocyte Antigen class (HLA) Ib family that induces tolerance, is associated with fewer rejections in solid-organ transplantation. In contrast to HLA-G, HLA antigen incompatibilities between donor and recipient can lead to rejection, except in liver transplantation. We compared HLA-G plasma levels and the presence of anti-HLA antibodies before and after LT to understand the low immunogenicity of the liver. We conducted a large prospective study that included 118 patients on HLA-G plasma levels during a 12-month follow-up and compared them to the status of anti-HLA antibodies. HLA-G plasma levels were evaluated by ELISA at seven defined pre- and post-LT time points. HLA-G plasma levels were stable over time pre-LT and were not associated with patient characteristics. The level increased until the third month post-LT, before decreasing to a level comparable to that of the pre-LT period at one year of follow-up. Such evolution was independent of biological markers and immunosuppressive treatment, except with glucocorticoids. An HLA-G plasma level ≤ 50 ng/ml on day 8 after LT was significantly associated with a higher rejection risk. We also observed a higher percentage of rejection in the presence of donor specific anti-HLA antibodies (DSA) and an association between the increase in HLA-G plasma levels at three months and the absence of DSA. The low immunogenicity of liver allografts could be related to early elevated levels of HLA-G, which lead, in turn, to a decrease in anti-HLA antibodies, opening potential new therapeutic strategies using synthetic HLA-G proteins.
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Affiliation(s)
- Bastien Le Floc’h
- Service de Chirurgie Digestive, Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, CHU Rennes, Univ Rennes, Rennes, France
| | - Nathalie Costet
- Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Univ Rennes, Rennes, France
| | - Nicolas Vu
- Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Univ Rennes, Rennes, France
| | - Pénélope Bernabeu-Gentey
- Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Univ Rennes, Rennes, France
| | - Charlotte Pronier
- Pôle de Biologie, Service de Virologie Générale et Rétrovirologie, Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, CHU Rennes, Univ Rennes, Rennes, France
| | - Pauline Houssel-Debry
- Service des Maladies du Foie (SMF), Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, CHU Rennes, Univ Rennes, Rennes, France
| | - Karim Boudjéma
- Service de Chirurgie Digestive, Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, CHU Rennes, Univ Rennes, Rennes, France
| | - Virginie Renac
- EFS Rennes, Laboratoire Histocompatibilité-Immunogénétique / Immunologie Leuco-plaquettaire (HLA/HPA), Rennes, France
| | - Michel Samson
- Inserm, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Univ Rennes, Rennes, France
| | - Laurence Amiot
- Pôle de Biologie, Laboratoire de Cytologie-Cytometrie en flux Inserm, EHESP, IRSET (Institut de Recherche en santé, Environnement et Travail) - UMR_S 1085, CHU Rennes, Univ Rennes, Rennes, France
- * E-mail:
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Wang W, Zhou X, Zhang Y, Chen Z, Huang J, Zhang X, Kwak-Kim J. The characteristics of antigenic specificity of memory regulatory t cells in women with unexplained recurrent pregnancy loss. J Reprod Immunol 2022; 154:103694. [PMID: 36063659 DOI: 10.1016/j.jri.2022.103694] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 07/22/2022] [Accepted: 08/11/2022] [Indexed: 12/14/2022]
Abstract
Regulatory T cells (Tregs) proliferate after encountering the fetal antigen, which plays an important role in maintaining maternal-fetal tolerance. Activated Tregs increase number and function after antigen encounter and develop memory. Upon subsequent antigen exposure, Treg cells re-expand more rapidly. However, the characteristics of memory regulatory T cells (mTregs) during normal pregnancy and unexplained recurrent pregnancy loss (URPL) have not been elucidated well. In this study, we analyzed the proportion of Tregs and mTregs in the peripheral blood and their surface expression of PD-1, CCR6, and HLA-G in normal non-pregnant (n = 20) and pregnant (n = 20) women, and non-pregnant (n = 20) and pregnant URPL (n = 20) women. We found that the proportions of mTregs in lymphocytes, CD3+ T cells, CD4+ T cells, and Tregs were lower in pregnant URPL patients than in normal pregnant women. The proportions of CD4+CD45RO+ Th cells in lymphocytes, CD3+ T, and CD4+ T cells in the pregnant URPL group were the highest among the four groups (P < 0.05). There were no significant differences among the other three groups (P > 0.05). The proportions of CD4+/CCR6+/mTregs, CD4+/PD-1+/mTregs, CD4+/HLA-G+/mTregs were significantly lower in the non-pregnant normal group and non-pregnant URPL group than in normal pregnant group and pregnant URPL group (P < 0.05, respectively). The proportions of CD4+/CCR6+ mTregs, CD4+/PD-1+/mTregs, CD4+/HLA-G+/mTregs were lower in pregnant URPL group than in normal pregnant group (P < 0.05, respectively). These findings indicate that fetal antigen-specific mTregs play an important role in pregnancy maintenance, and the dysregulation of mTreg may contribute to URPL.
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Affiliation(s)
- Wenjuan Wang
- Reproduction Medical Center, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, PR China; Reproduction Medical Center, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai 264000, PR China.
| | - Xiaojiao Zhou
- Department of Clinical Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai 264000, PR China; School of Medicine, Qingdao Universityō, 38 Dengzhou Road, Qingdao 266000, PR China
| | - Yi Zhang
- Reproduction Medical Center, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, PR China
| | - Zeyang Chen
- Reproduction Medical Center, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, PR China; Department of Gynecology, Weihai Central Hospital, 3 Mishan East Road, Weihai 264400, PR China
| | - Jinxia Huang
- Department of Clinical Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai 264000, PR China
| | - Xiaolu Zhang
- Department of Clinical Laboratory, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, 20 Yuhuangding East Road, Yantai 264000, PR China
| | - Joanne Kwak-Kim
- Reproductive Medicine and Immunology, Obstetrics and Gynecology, Clinical Sciences Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Vernon Hills, IL 60061, USA; Center for Cancer Cell Biology, Immunology and Infection, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
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8
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Liu S, Bos NA, Verschuuren EAM, van Baarle D, Westra J. Biological Characteristics of HLA-G and Its Role in Solid Organ Transplantation. Front Immunol 2022; 13:902093. [PMID: 35769475 PMCID: PMC9234285 DOI: 10.3389/fimmu.2022.902093] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/19/2022] [Indexed: 11/18/2022] Open
Abstract
Organ transplantation is a lifesaving option for patients with advanced diseases. Rejection is regarded as one of the most severe risk factors post-transplantation. A molecule that contributes to immune tolerance and resisting rejection is human leukocyte antigen (HLA)-G, which belongs to the non-classical major histocompatibility complex class (MHC) I family. HLA-G was originally found to play a role during pregnancy to maintain immune tolerance between mother and child. It is expressed in the placenta and detected in several body fluids as soluble factor as well as different membrane isoforms on cells. Recent findings on HLA-G show that it can also play multifaceted roles during transplantation. This review will explain the general characteristics and biological function of HLA-G and summarize the views supporting the tolerogenic and other roles of HLA-G to better understand its role in solid organ transplantation (SOT) and its complications. Finally, we will discuss potential future research on the role of HLA-G in prevention, diagnosis, and treatment in SOT.
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Affiliation(s)
- Siqi Liu
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Nicolaas A. Bos
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Erik A. M. Verschuuren
- Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Debbie van Baarle
- Department of Medical Microbiology and Infection Prevention, University Medical Center Groningen, Groningen, Netherlands
| | - Johanna Westra
- Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- *Correspondence: Johanna Westra,
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Khamri W, Gudd C, Liu T, Nathwani R, Krasniqi M, Azam S, Barbera T, Trovato FM, Possamai L, Triantafyllou E, Seoane RC, Lebosse F, Singanayagam A, Kumar N, Bernsmeier C, Mukherjee S, McPhail M, Weston CJ, Antoniades CG, Thursz MR. Suppressor CD4 + T cells expressing HLA-G are expanded in the peripheral blood from patients with acute decompensation of cirrhosis. Gut 2022; 71:1192-1202. [PMID: 34344786 PMCID: PMC9120410 DOI: 10.1136/gutjnl-2021-324071] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 07/22/2021] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Identifying components of immuneparesis, a hallmark of chronic liver failure, is crucial for our understanding of complications in cirrhosis. Various suppressor CD4+ T cells have been established as potent inhibitors of systemic immune activation. Here, we establish the presence, regulation and mechanism of action of a suppressive CD4+ T cell subset expressing human leucocyte antigen G (HLA-G) in patients with acute decompensation of cirrhosis (AD). DESIGN Flow cytometry was used to determine the proportion and immunophenotype of CD4+HLA-G+ T cells from peripheral blood of 20 healthy controls (HCs) and 98 patients with cirrhosis (28 with stable cirrhosis (SC), 20 with chronic decompensated cirrhosis (CD) and 50 with AD). Transcriptional and functional signatures of cell-sorted CD4+HLA-G+ cells were delineated by NanoString technology and suppression assays, respectively. The role of immunosuppressive cytokine interleukin (IL)-35 in inducing this population was investigated through in vitro blockade experiments. Immunohistochemistry (IHC) and cultures of primary human Kupffer cells (KCs) were performed to assess cellular sources of IL-35. HLA-G-mediated T cell suppression was explored using neutralising antibodies targeting co-inhibitory pathways. RESULTS Patients with AD were distinguished by an expansion of a CD4+HLA-G+CTLA-4+IL-35+ immunosuppressive population associated with disease severity, clinical course of AD, infectious complications and poor outcome. Transcriptomic analyses excluded the possibility that these were thymic-derived regulatory T cells. IHC analyses and in vitro cultures demonstrate that KCs represent a potent source of IL-35 which can induce the observed HLA-G+ phenotype. These exert cytotoxic T lymphocyte antigen-4-mediated impaired responses in T cells paralleled by an HLA-G-driven downregulation of T helper 17-related cytokines. CONCLUSION We have identified a cytokine-driven peripherally derived suppressive population that may contribute to immuneparesis in AD.
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Affiliation(s)
- Wafa Khamri
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Cathrin Gudd
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Tong Liu
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Rooshi Nathwani
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Marigona Krasniqi
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Sofia Azam
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Thomas Barbera
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Francesca M Trovato
- Department of Inflammation Biology, Institute of Liver Studies, King’s College London, London, UK
| | - Lucia Possamai
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Evangelos Triantafyllou
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Rocio Castro Seoane
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Fanny Lebosse
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Arjuna Singanayagam
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Naveenta Kumar
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Christine Bernsmeier
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK,Department of Inflammation Biology, Institute of Liver Studies, King’s College London, London, UK
| | - Sujit Mukherjee
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Mark McPhail
- Department of Inflammation Biology, Institute of Liver Studies, King’s College London, London, UK
| | - Chris J Weston
- NIHR Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - Charalambos Gustav Antoniades
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Mark R Thursz
- Section of Hepatology & Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
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10
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Bucova M, Kluckova K, Kozak J, Rychly B, Suchankova M, Svajdler M, Matejcik V, Steno J, Zsemlye E, Durmanova V. HLA-G 14bp Ins/Del Polymorphism, Plasma Level of Soluble HLA-G, and Association with IL-6/IL-10 Ratio and Survival of Glioma Patients. Diagnostics (Basel) 2022; 12:1099. [PMID: 35626255 PMCID: PMC9139224 DOI: 10.3390/diagnostics12051099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/14/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022] Open
Abstract
HLA-G is an immune checkpoint molecule with immunosuppressive and anti-inflammatory activities, and its expression and level of its soluble form (sHLA-G) may play an important role in tumor prognosis. The HLA-G 14bp ins/del polymorphism and the plasma level of soluble HLA-G (sHLA-G) were investigated by a polymerase chain reaction and ELISA, respectively, in 59 glioma patients. A significantly higher proportion of glioma patients had the 14 nt insert in both homozygous and heterozygous states compared to the control group. Glioma patients also had higher plasma levels of sHLA-G. Patients with methylated MGMT promoters had lower levels of sHLA-G than those with unmethylated MGMT promoters. The level of sHLA-G negatively correlated with the overall survival of patients. Glioblastoma patients who survived more than one year after diagnosis had lower levels of sHLA-G than those surviving less than one year. Patients with sHLA-G levels below the cut-off value of 40 U/mL survived significantly longer than patients with sHLA-G levels above 40 U/mL. The levels of sHLA-G were also negatively correlated with the level of IL-6 (p = 0.0004) and positively with IL-10/IL-6 (p = 0.046). Conclusion: The presence of the 14 nt insert in both homozygous and heterozygous states of the HLA-G 14bp ins/del polymorphism is more frequent in glioma patients and the elevated plasma levels of sHLA-G are negatively associated with their survival.
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Affiliation(s)
- Maria Bucova
- Faculty of Medicine, Institute of Immunology, Comenius University, 813 72 Bratislava, Slovakia; (K.K.); (M.S.); (E.Z.); (V.D.)
| | - Kristina Kluckova
- Faculty of Medicine, Institute of Immunology, Comenius University, 813 72 Bratislava, Slovakia; (K.K.); (M.S.); (E.Z.); (V.D.)
| | - Jan Kozak
- Department of Neurosurgery, Faculty of Medicine, Comenius University and University Hospital, 833 05 Bratislava, Slovakia; (J.K.); (V.M.); (J.S.)
| | - Boris Rychly
- Alpha Medical, Ltd., 841 01 Bratislava, Slovakia;
| | - Magda Suchankova
- Faculty of Medicine, Institute of Immunology, Comenius University, 813 72 Bratislava, Slovakia; (K.K.); (M.S.); (E.Z.); (V.D.)
| | - Marian Svajdler
- Cytopathos Ltd., 831 03 Bratislava, Slovakia;
- Sikl’s Department of Pathology, the Faculty of Medicine and Faculty Hospital in Pilsen, Charles University, 306 05 Pilsen, Czech Republic
| | - Viktor Matejcik
- Department of Neurosurgery, Faculty of Medicine, Comenius University and University Hospital, 833 05 Bratislava, Slovakia; (J.K.); (V.M.); (J.S.)
| | - Juraj Steno
- Department of Neurosurgery, Faculty of Medicine, Comenius University and University Hospital, 833 05 Bratislava, Slovakia; (J.K.); (V.M.); (J.S.)
| | - Eszter Zsemlye
- Faculty of Medicine, Institute of Immunology, Comenius University, 813 72 Bratislava, Slovakia; (K.K.); (M.S.); (E.Z.); (V.D.)
| | - Vladimira Durmanova
- Faculty of Medicine, Institute of Immunology, Comenius University, 813 72 Bratislava, Slovakia; (K.K.); (M.S.); (E.Z.); (V.D.)
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11
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Mestrallet G, Carosella ED, Martin MT, Rouas-Freiss N, Fortunel NO, LeMaoult J. Immunosuppressive Properties of Epidermal Keratinocytes Differ According to Their Immaturity Status. Front Immunol 2022; 13:786859. [PMID: 35222373 PMCID: PMC8878806 DOI: 10.3389/fimmu.2022.786859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 01/14/2022] [Indexed: 12/04/2022] Open
Abstract
Preservation of a functional keratinocyte stem cell pool is essential to ensure the long-term maintenance of epidermis integrity, through continuous physiological renewal and regeneration in case of injury. Protecting stem cells from inflammation and immune reactions is thus a critical issue that needs to be explored. Here, we show that the immature CD49fhigh precursor cell fraction from interfollicular epidermis keratinocytes, comprising stem cells and progenitors, is able to inhibit CD4+ T-cell proliferation. Of note, both the stem cell-enriched CD49fhigh/EGFRlow subpopulation and the less immature CD49fhigh/EGFRhigh progenitors ensure this effect. Moreover, we show that HLA-G and PD-L1 immune checkpoints are overexpressed in CD49fhigh precursors, as compared to CD49flow differentiated keratinocytes. This potency may limit immune reactions against immature precursors including stem cells, and protect them from exacerbated inflammation. Further exploring this correlation between immuno-modulation and immaturity may open perspectives in allogenic cell therapies.
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Affiliation(s)
- Guillaume Mestrallet
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
| | - Edgardo D. Carosella
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Michele T. Martin
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
| | - Nathalie Rouas-Freiss
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
| | - Nicolas O. Fortunel
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Evry, France
- Université Paris-Saclay, Saint-Aubin, France
- *Correspondence: Joel LeMaoult, ; Nicolas O. Fortunel,
| | - Joel LeMaoult
- Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, Paris, France
- U976 HIPI Unit, IRSL, Université Paris, Paris, France
- *Correspondence: Joel LeMaoult, ; Nicolas O. Fortunel,
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12
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Al Malki J, Ahmed N. Epidemiological and histomorphic studies in sheep infected with hydatid cyst in Taif area. Saudi J Biol Sci 2022; 29:886-893. [PMID: 35197756 PMCID: PMC8847970 DOI: 10.1016/j.sjbs.2021.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 11/15/2022] Open
Abstract
Hydatidosis is a zoonotic disease caused by Echinococcus granulosus larvae, which affects sheep worldwide, especially in rural communities. This study aims to determine the prevalence and structure of hydatid cyst in sheep. A total number of 1,198 sheep in different age groups G1 (<1 year), G2 (1–2 years) and G3 (>2 years) were slaughtered at Taif abattoirs, then examined for the presence of hydatid cysts in lung, liver, and mesentery. Prevalence of hydatid cyst infection in imported sheep (13.0%) was higher than of local sheep (10.2%). Particularly, as per gender, prevalence of imported females (71.9%) was higher than those of local females (28.1%), while that of imported males (66.3%) was higher than those of local males (33.7%). Large sizes of hydatid cysts and fertility recorded in G3 were higher in both local and imported sheep than those of G1 and G2. Morphometric analysis of pathological lesions in liver of all infected sheep showed a significant increase compared to non-infected healthy sheep (have no lesions) (P < 0.001). In addition, for all infected sheep, histochemical investigation with Masson’s trichrome stain showed collagen fibers inside the hydatid cyst capsules and in pericystic region. The collagen fibers content and the cellular laminated membranes took the green color, while immunohistochemical evaluation detected a positive reaction for CD3.
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13
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Martín-Villa JM, Vaquero-Yuste C, Molina-Alejandre M, Juarez I, Suárez-Trujillo F, López-Nares A, Palacio‐Gruber J, Barrera-Gutiérrez L, Fernández-Cruz E, Rodríguez-Sainz C, Arnaiz-Villena A. HLA-G: Too Much or Too Little? Role in Cancer and Autoimmune Disease. Front Immunol 2022; 13:796054. [PMID: 35154112 PMCID: PMC8829012 DOI: 10.3389/fimmu.2022.796054] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 01/05/2022] [Indexed: 12/12/2022] Open
Abstract
HLA-G is a non-classical HLA class I molecule with immunomodulatory properties. It was initially described at the maternal-fetal interface, and it was later found that this molecule was constitutively expressed on certain immuneprivileged tissues, such as cornea, endothelial and erythroid precursors, and thymus. The immunosuppressive effect of HLA-G is exerted through the interaction with its cognate receptors, expressed on immunocompetent cells, like ILT2, expressed on NK, B, T cells and APCs; ILT4, on APCs; KIR, found on the surface of NK cells; and finally, the co-receptor CD8. Because of these immunomodulatory functions, HLA-G has been involved in several processes, amongst which organ transplantation, viral infections, cancer progression, and autoimmunity. HLA-G neo-expression on tumors has been recently described in several types of malignancies. In fact, tumor progression is tightly linked to the presence of the molecule, as it exerts its tolerogenic function, inhibiting the cells of the immune system and favoring tumor escape. Several polymorphisms in the 3'UTR region condition changes in HLA-G expression (14bp and +3142C/G, among others), which have been associated with both the development and outcome of patients with different tumor types. Also, in recent years, several studies have shown that HLA-G plays an important role in the control of autoimmune diseases. The ability of HLA-G to limit the progression of these diseases has been confirmed and, in fact, levels of the molecule and several of its polymorphisms have been associated with increased susceptibility to the development of autoimmune diseases, as well as increased disease severity. Thus, modulating HLA-G expression in target tissues of oncology patients or patients with autoimmune diseases may be potential therapeutic approaches to treat these pathological conditions.
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Affiliation(s)
- José Manuel Martín-Villa
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Christian Vaquero-Yuste
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Marta Molina-Alejandre
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Ignacio Juarez
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Fabio Suárez-Trujillo
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Adrián López-Nares
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - José Palacio‐Gruber
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Luis Barrera-Gutiérrez
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Eduardo Fernández-Cruz
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Servicio de Inmunología, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Carmen Rodríguez-Sainz
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Servicio de Inmunología, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Antonio Arnaiz-Villena
- Departamento de Inmunología, Oftalmología y ORL, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
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14
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Sun YX, Feng Q, Wang SW, Li X, Sheng Z, Peng J. HLA-G-ILT2 interaction contributes to suppression of bone marrow B cell proliferation in acquired aplastic anemia. Ann Hematol 2022; 101:739-748. [PMID: 35041051 DOI: 10.1007/s00277-022-04757-3] [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: 01/02/2021] [Accepted: 01/09/2022] [Indexed: 12/17/2022]
Abstract
Acquired aplastic anemia (AA) is an autoimmune disease characterized by hematopoietic stem and progenitor cell destruction in bone marrow. The non-classic human leukocyte class I antigen (HLA-) G interacts with multiple cell subsets, such as T cells and B cells. HLA-G exerts powerful immune suppression by binding with its receptors, immunoglobulin-like transcripts (ILTs). Here, we compared 46 AA patients and 28 healthy controls. Soluble HLA-G levels in bone marrow supernatants from AA patients were higher than controls. The proportion of bone marrow B cells was decreased and the ILT2-expressing cells among CD19+ cells were increased in AA patients. In addition, the percentage of mature B cells among marrow B cells was increased in AA patient, while the percentage of pro-B plus pre-B cells was decreased. More immature B cells and pro-B plus pre-B cells expressed ILT2 in AA patients than in controls, while mature B cells expressing ILT2 did not differ significantly. Functional studies demonstrated that high-level soluble HLA-G inhibited bone marrow B cell proliferation by interacting with ILT2 in AA, and was blocked by anti-HLA-G and anti-ILT2 monoclonal antibodies. Together, these results suggest that the abnormal decrease of pro-B plus pre-B cells in AA patients was related to the enhanced suppression by the excess HLA-G and ILT2 proteins. Therapeutic blockade of the HLA-G-ILT2 interaction may help to normalize bone marrow B cell proliferation.
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Affiliation(s)
- Yuan-Xin Sun
- Department of Hemodialysis, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qi Feng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shu-Wen Wang
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xin Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zi Sheng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. .,School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Jun Peng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. .,State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
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15
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Tumor infiltrating and peripheral CD4 +ILT2 + T cells are a cytotoxic subset selectively inhibited by HLA-G in clear cell renal cell carcinoma patients. Cancer Lett 2021; 519:105-116. [PMID: 34186161 DOI: 10.1016/j.canlet.2021.06.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/13/2021] [Accepted: 06/20/2021] [Indexed: 12/13/2022]
Abstract
HLA-G ILT2 has recently been positioned as a major immune checkpoint in urologic cancers. In clear cell renal cell carcinoma (ccRCC), tumor-infiltrating CD8+ T cells expressing ILT2 are a highly cytotoxic cell population, distinct from PD1+ T cells, and whose function is inhibited by HLA-G+ targets. Here we report that ILT2 receptor can also be expressed by CD4+ T cells in urologic cancer patients. In the course of deciphering the role of these ILT2+CD4+ T cells, we found a statistical association between the tumor context and these T cells, and a positive correlation between the levels of peripheral and intra-tumoral CD4+ILT2+ T cells. Phenotypic analyses revealed that CD4+ILT2+ T cells express memory T cell (CD27-CD28-CD57+) and cytotoxicity (Tbet+Perforin+KLRG1+NKp80+GPR56+) markers, consistent with a CD4+CTL phenotype. Functional assays showed that ccRCC-infiltrating CD4+ILT2+ T cells indeed have high cytolytic properties and therefore function as proper CD4+CTLs, but are selectively inhibited by HLA-G+ targets. Clinical relevance was provided by immunohistochemical analyses on ccRCC tumor lesions with HLA-G+ HLA class II+ tumor cells next to CD4+ T cell infiltrates. Our findings provide evidence supporting that ILT2+ T cells constitute a reservoir of intratumor cytotoxic T cells that is not targeted by the current checkpoint inhibitors, but could be by anti-HLA-G/anti-ILT2 antibodies as novel immunotherapy in HLA-G+ tumors.
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16
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Mestrallet G, Auvré F, Schenowitz C, Carosella ED, LeMaoult J, Martin MT, Rouas-Freiss N, Fortunel NO. Human Keratinocytes Inhibit CD4 + T-Cell Proliferation through TGFB1 Secretion and Surface Expression of HLA-G1 and PD-L1 Immune Checkpoints. Cells 2021; 10:cells10061438. [PMID: 34201301 PMCID: PMC8227977 DOI: 10.3390/cells10061438] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 01/18/2023] Open
Abstract
Human skin protects the body against infection and injury. This protection involves immune and epithelial cells, but their interactions remain largely unknown. Here, we show that cultured epidermal keratinocytes inhibit allogenic CD4+ T-cell proliferation under both normal and inflammatory conditions. Inhibition occurs through the secretion of soluble factors, including TGFB1 and the cell-surface expression of HLA-G1 and PD-L1 immune checkpoints. For the first time, we here describe the expression of the HLA-G1 protein in healthy human skin and its role in keratinocyte-driven tissue immunomodulation. The overexpression of HLA-G1 with an inducible vector increased the immunosuppressive properties of keratinocytes, opening up perspectives for their use in allogeneic settings for cell therapy.
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Affiliation(s)
- Guillaume Mestrallet
- CEA, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Francois Jacob Institute of Biology, DRF, 91000 Evry, France; (G.M.); (F.A.)
- Université Paris-Saclay, 91190 Saint-Aubin, France
| | - Frédéric Auvré
- CEA, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Francois Jacob Institute of Biology, DRF, 91000 Evry, France; (G.M.); (F.A.)
- Université Paris-Saclay, 91190 Saint-Aubin, France
| | - Chantal Schenowitz
- CEA, DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, 75010 Paris, France; (C.S.); (E.D.C.)
- U976 HIPI Unit, IRSL, Université Paris, 75010 Paris, France
| | - Edgardo D. Carosella
- CEA, DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, 75010 Paris, France; (C.S.); (E.D.C.)
- U976 HIPI Unit, IRSL, Université Paris, 75010 Paris, France
| | - Joel LeMaoult
- CEA, DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, 75010 Paris, France; (C.S.); (E.D.C.)
- U976 HIPI Unit, IRSL, Université Paris, 75010 Paris, France
- Correspondence: (J.L.); (M.T.M.); (N.R.-F.); (N.O.F.); Tel.: +33-1-60-87-34-91 (M.T.M.); +33-1-57-27-68-01 (N.R.-F.); +33-1-60-87-34-92 (N.O.F.)
| | - Michèle T. Martin
- CEA, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Francois Jacob Institute of Biology, DRF, 91000 Evry, France; (G.M.); (F.A.)
- Université Paris-Saclay, 91190 Saint-Aubin, France
- Correspondence: (J.L.); (M.T.M.); (N.R.-F.); (N.O.F.); Tel.: +33-1-60-87-34-91 (M.T.M.); +33-1-57-27-68-01 (N.R.-F.); +33-1-60-87-34-92 (N.O.F.)
| | - Nathalie Rouas-Freiss
- CEA, DRF, Francois Jacob Institute of Biology, Hemato-Immunology Research Department, Saint-Louis Hospital, 75010 Paris, France; (C.S.); (E.D.C.)
- U976 HIPI Unit, IRSL, Université Paris, 75010 Paris, France
- Correspondence: (J.L.); (M.T.M.); (N.R.-F.); (N.O.F.); Tel.: +33-1-60-87-34-91 (M.T.M.); +33-1-57-27-68-01 (N.R.-F.); +33-1-60-87-34-92 (N.O.F.)
| | - Nicolas O. Fortunel
- CEA, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Institute of Cellular and Molecular Radiobiology, Francois Jacob Institute of Biology, DRF, 91000 Evry, France; (G.M.); (F.A.)
- Université Paris-Saclay, 91190 Saint-Aubin, France
- Correspondence: (J.L.); (M.T.M.); (N.R.-F.); (N.O.F.); Tel.: +33-1-60-87-34-91 (M.T.M.); +33-1-57-27-68-01 (N.R.-F.); +33-1-60-87-34-92 (N.O.F.)
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Darbas S, Yilmaz VT, Kocak H, Kisaoglu A, Demiryilmaz I, Aydinli B, Arslan HS, Ucar F. New markers for predictions of acute and chronic rejection and graft outcomes in kidney transplant recipients; HLA-G gene 3'UTR 14 bp polymorphism and sHLA-G. Gene 2021; 790:145712. [PMID: 33984446 DOI: 10.1016/j.gene.2021.145712] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 04/19/2021] [Accepted: 05/06/2021] [Indexed: 01/10/2023]
Abstract
The aim of this study was to evaluate the relation of Human Leukocyte Antigen-G (HLA-G) 14 bp ins/del (insertion/deletion) polymorphism and soluble HLA-G (sHLA-G) level with rejection in kidney transplant recipients. The study was planned as a case-control study involving two hundred fifty kidney transplant recipients. The case group consisted of 125 (female/male: 56/69) kidney transplant recipients diagnosed with acute (n = 52) and chronic rejection (n = 73). The control group consisted of one hundred twenty-five kidney transplant patients with no acute or chronic rejection matched by gender and age in the case group. The sHLA-G level in the recipient's plasma (at the time of rejection for the case, the same time as the case after the transplant for control) was analyzed by Enzyme-Linked Immunosorbent Assay (ELISA). HLA-G 3' untranslated region (3'UTR) polymorphism of recipient and donor was determined using agarose gel electrophoresis and DNA sequencing method. In our study, it was shown that acute rejection rate increased 1.06 times and chronic rejection rate increased 1.14 times in kidney transplant recipients with low serum sHLA-G levels. The rejection patients with the HLA-G 14 bp del/del genotype had higher sHLA-G levels post-transplantation. The frequency of acute rejection was lower in patients with HLA-G 14 bp del/del polymorphism than those with ins/ins and ins/del polymorphisms. This study proposes that HLA-G 3'UTR polymorphism and sHLA-G level might be useful in prediction of rejection in kidney transplant recipients.
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Affiliation(s)
- Sule Darbas
- Department of Medical Biology and Genetics, Akdeniz University Faculty of Medicine, Antalya, Turkey.
| | - Vural Taner Yilmaz
- Division of Nephrology, Department of Internal Medicine, Akdeniz University Faculty of Medicine, Antalya, Turkey; Tuncer Karpuzoglu Transplantation Center, Akdeniz University Hospital, Antalya, Turkey.
| | - Huseyin Kocak
- Division of Nephrology, Department of Internal Medicine, Akdeniz University Faculty of Medicine, Antalya, Turkey; Tuncer Karpuzoglu Transplantation Center, Akdeniz University Hospital, Antalya, Turkey.
| | - Abdullah Kisaoglu
- Department of General Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey; Tuncer Karpuzoglu Transplantation Center, Akdeniz University Hospital, Antalya, Turkey.
| | - Ismail Demiryilmaz
- Department of General Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey; Tuncer Karpuzoglu Transplantation Center, Akdeniz University Hospital, Antalya, Turkey.
| | - Bulent Aydinli
- Department of General Surgery, Akdeniz University Faculty of Medicine, Antalya, Turkey; Tuncer Karpuzoglu Transplantation Center, Akdeniz University Hospital, Antalya, Turkey.
| | - Habibe Sema Arslan
- Department of Medical Biology and Genetics, Akdeniz University Faculty of Medicine, Antalya, Turkey.
| | - Fahri Ucar
- Department of Medical Biology and Genetics, Akdeniz University Faculty of Medicine, Antalya, Turkey; Tuncer Karpuzoglu Transplantation Center, Akdeniz University Hospital, Antalya, Turkey.
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18
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Anna F, Bole-Richard E, LeMaoult J, Escande M, Lecomte M, Certoux JM, Souque P, Garnache F, Adotevi O, Langlade-Demoyen P, Loustau M, Caumartin J. First immunotherapeutic CAR-T cells against the immune checkpoint protein HLA-G. J Immunother Cancer 2021; 9:e001998. [PMID: 33737343 PMCID: PMC7978334 DOI: 10.1136/jitc-2020-001998] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/15/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND CAR-T cells immunotherapy is a breakthrough in the treatment of hematological malignancies such as acute lymphoblastic leukemia (ALL) and B-cell malignancies. However, CAR-T therapies face major hurdles such as the lack of tumor-specific antigen (TSA), and immunosuppressive tumor microenvironment sometimes caused by the tumorous expression of immune checkpoints (ICPs) such as HLA-G. Indeed, HLA-G is remarkable because it is both a potent ICP and a TSA. HLA-G tumor expression causes immune escape by impairing innate and adaptive immune responses and by inducing a suppressive microenvironment. Yet, to date, no immunotherapy targets it. METHODS We have developed two anti-HLA-G third-generation CARs based on new anti-HLA-G monoclonal antibodies. RESULTS Anti-HLA-G CAR-T cells were specific for immunosuppressive HLA-G isoforms. HLA-G-activated CAR-T cells polarized toward T helper 1, and became cytotoxic against HLA-G+ tumor cells. In vivo, anti-HLA-G CAR-T cells were able to control and eliminate HLA-G+ tumor cells. The interaction of tumor-HLA-G with interleukin (IL)T2-expressing T cells is known to result in effector T cell functional inhibition, but anti-HLA-G CAR-T cells were insensitive to this inhibition and still exerted their function even when expressing ILT2. Lastly, we show that anti-HLA-G CAR-T cells differentiated into long-term memory effector cells, and seemed not to lose function even after repeated stimulation by HLA-G-expressing tumor cells. CONCLUSION We report for the first time that HLA-G, which is both a TSA and an ICP, constitutes a valid target for CAR-T cell therapy to specifically target and eliminate both tumor cells and HLA-G+ suppressive cells.
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MESH Headings
- Animals
- Antibodies, Monoclonal/genetics
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/metabolism
- Antigens, CD/metabolism
- Cell Differentiation
- Coculture Techniques
- Cytotoxicity, Immunologic
- HLA-G Antigens/immunology
- HLA-G Antigens/metabolism
- Humans
- Immunologic Memory
- Immunotherapy, Adoptive
- K562 Cells
- Leukemia, Erythroblastic, Acute/genetics
- Leukemia, Erythroblastic, Acute/immunology
- Leukemia, Erythroblastic, Acute/metabolism
- Leukemia, Erythroblastic, Acute/therapy
- Leukocyte Immunoglobulin-like Receptor B1/metabolism
- Memory T Cells/immunology
- Memory T Cells/metabolism
- Memory T Cells/transplantation
- Mice, Inbred NOD
- Mice, SCID
- Phenotype
- Receptors, Chimeric Antigen/genetics
- Receptors, Chimeric Antigen/metabolism
- Time Factors
- Tumor Microenvironment
- Xenograft Model Antitumor Assays
- Mice
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Affiliation(s)
- François Anna
- Preclinical Department, Invectys, Paris, France
- Molecular Virology and Vaccinology Unit, Virology Department, Pasteur Institute, Paris, Île-de-France, France
| | - Elodie Bole-Richard
- INSERM UMR1098 RIGHT Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besancon, Franche-Comté, France
- Université Bourgogne Franche-Comté, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, Besançon, France
| | - Joel LeMaoult
- Service de Recherche en Hémato-Immunologie (SRHI), CEA, Paris, France
- Université de Paris, Paris, Île-de-France, France
| | | | | | - Jean-Marie Certoux
- INSERM UMR1098 RIGHT Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besancon, Franche-Comté, France
- Université Bourgogne Franche-Comté, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, Besançon, France
| | - Philippe Souque
- Molecular Virology and Vaccinology Unit, Virology Department, Pasteur Institute, Paris, Île-de-France, France
| | - Francine Garnache
- INSERM UMR1098 RIGHT Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besancon, Franche-Comté, France
- Université Bourgogne Franche-Comté, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, Besançon, France
| | - Olivier Adotevi
- INSERM UMR1098 RIGHT Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besancon, Franche-Comté, France
- Université Bourgogne Franche-Comté, Besançon, France
- Etablissement Français du Sang Bourgogne Franche-Comté, Besançon, France
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19
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Kumano S, Okushi Y, Fujimoto K, Adachi H, Furuichi K, Yokoyama H. Role and expression of non-classical human leukocyte antigen-G in renal transplanted allografts. Clin Exp Nephrol 2021; 25:428-438. [PMID: 33398603 DOI: 10.1007/s10157-020-01999-1] [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: 08/04/2020] [Accepted: 11/19/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND The non-classical class I molecule human leukocyte antigen-G (HLA-G) has great potential to modulate the immune response. However, the mechanism underlying HLA-G induction remains unknown. Therefore, this study aimed to determine the factors that induce HLA-G expression on proximal tubular epithelial cells (pTECs) in renal transplanted allografts in vivo and in vitro. METHODS This study included 40 adult Japanese patients with renal allografts (35 and five patients with kidneys from living and deceased donors, respectively) who survived for at least 1 year. We evaluated HLA-G1/5 expression using an immunofluorescence method and investigated the induction of HLA-G expression in primary cultured human pTECs by cytokines and immunosuppressants. RESULTS The HLA-G expression was identified in the perinuclear region or on the basement membrane of pTECs of renal biopsy tissue in 12 (30%) of 40 patients at 2-4 weeks and at 1 year following transplantation. A reduction of 30% in the estimated glomerular filtration rate was lower in the HLA-G-positive group than that of the negative group (p = 0.016). Cox proportional hazard models also demonstrated that HLA-G1/5 expression on pTECs was an independent predictor of improved renal allograft function (hazard ratio, 0.189; 95% CI 0.041-0.850, p = 0.030). Interferon-beta was the most powerful inducer of HLA-G expression in vitro, whereas the immunosuppressants everolimus, tacrolimus, cyclosporin, and dexamethasone did not induce any expression. CONCLUSION Unlike immunosuppressants, acquired HLA-G expression might confer long-term renal preservation effects in renal transplanted allografts.
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Affiliation(s)
- Sho Kumano
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
| | - Yuki Okushi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Keiji Fujimoto
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Hiroki Adachi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Kengo Furuichi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Hitoshi Yokoyama
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
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20
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Liu L, Wang L, Zhao L, He C, Wang G. The Role of HLA-G in Tumor Escape: Manipulating the Phenotype and Function of Immune Cells. Front Oncol 2020; 10:597468. [PMID: 33425752 PMCID: PMC7786297 DOI: 10.3389/fonc.2020.597468] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022] Open
Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class I (MHC I) molecule, and under physiological conditions, its expression is strictly restricted to the maternal–fetal interface and immune-privileged organs where HLA-G is expected to contribute to establishment and maintenance of immune tolerance. However, the expression of HLA-G has been found in various types of tumors, and the level of its expression frequently correlates with high-grade histology and poor prognosis, raising the possibility that it may play a negative role in tumor immunity. ILT2 and ILT4, present on a broad of immune cells, have been identified as the main receptors engaging HLA-G, and their interactions have been found to allow the conversion of effectors like NK cells and T cells to anergic or unresponsive state, activated DCs to tolerogenic state, and to drive the differentiation of T cells toward suppressive phenotype. Therefore, tumors can employ HLA-G to modulate the phenotype and function of immune cells, allowing them to escape immune attack. In this review, we discuss the mechanism underlying HLA-G expression and function, its role played in each step of the tumor-immunity cycle, as well as the potential to target it for therapeutic benefit.
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Affiliation(s)
- Lu Liu
- Department of Gastroenterology, Center for Digestive Diseases, People's Hospital of Baoan District, The 8th People's Hospital of Shenzhen, Shenzhen, China.,Department of Critical Care Medicine, People's Hospital of Baoan District, The 8th People's Hospital of Shenzhen, Shenzhen, China
| | - Lijun Wang
- Department of Critical Care Medicine, People's Hospital of Baoan District, The 8th People's Hospital of Shenzhen, Shenzhen, China
| | - Lihong Zhao
- Department of Spine Surgery, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Chen He
- Department of Ophthalmology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Ganlu Wang
- Department of Gastroenterology, Center for Digestive Diseases, People's Hospital of Baoan District, The 8th People's Hospital of Shenzhen, Shenzhen, China
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21
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Tanimine N, Ohira M, Tahara H, Ide K, Tanaka Y, Onoe T, Ohdan H. Strategies for Deliberate Induction of Immune Tolerance in Liver Transplantation: From Preclinical Models to Clinical Application. Front Immunol 2020; 11:1615. [PMID: 32849546 PMCID: PMC7412931 DOI: 10.3389/fimmu.2020.01615] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/17/2020] [Indexed: 12/12/2022] Open
Abstract
The liver exhibits intrinsic immune regulatory properties that maintain tolerance to endogenous and exogenous antigens, and provide protection against pathogens. Such an immune privilege contributes to susceptibility to spontaneous acceptance despite major histocompatibility complex mismatch when transplanted in animal models. Furthermore, the presence of a liver allograft can suppress the rejection of other solid tissue/organ grafts from the same donor. Despite this immune privilege of the livers, to control the undesired alloimmune responses in humans, most liver transplant recipients require long-term treatment with immune-suppressive drugs that predispose to cardiometabolic side effects and renal insufficiency. Understanding the mechanism of liver transplant tolerance and crosstalk between a variety of hepatic immune cells, such as dendritic cells, Kupffer cells, liver sinusoidas endothelial cells, hepatic stellate cells and so on, and alloreactive T cells would lead to the development of strategies for deliberate induction of more specific immune tolerance in a clinical setting. In this review article, we focus on results derived from basic studies that have attempted to elucidate the immune modulatory mechanisms of liver constituent cells and clinical trials that induced immune tolerance after liver transplantation by utilizing the immune-privilege potential of the liver.
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Affiliation(s)
- Naoki Tanimine
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Medical Center for Translational and Clinical Research Hiroshima University Hospital, Hiroshima, Japan
| | - Hiroyuki Tahara
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kentaro Ide
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takashi Onoe
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Kure Medical Center and Chugoku Cancer Center, National Hospital Organization, Kure, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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22
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Xu HH, Yan WH, Lin A. The Role of HLA-G in Human Papillomavirus Infections and Cervical Carcinogenesis. Front Immunol 2020; 11:1349. [PMID: 32670296 PMCID: PMC7330167 DOI: 10.3389/fimmu.2020.01349] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/27/2020] [Indexed: 12/24/2022] Open
Abstract
Human leukocyte antigen (HLA)-G, a non-classical HLA-class I molecule, has a low polymorphism frequency, restricted tissue distribution and immunoinhibitory property. HLA-G expression in tumor cells and cells chronically infected with virus may enable them to escape from host immune surveillance. It is well-known that the HLA-G molecule is a novel biomarker and potential therapeutic target that is relevant in various types of cancers, but its role in cervical cancer has not been fully explored. In this review, we aim to summarize and discuss the immunologic role of the HLA-G molecule in the context of HPV infections and the process of cervical cancer carcinogenesis. A better understanding of the potential impact of HLA-G on the clinical course of persistent HPV infections, cervical epithelial cell transformation, tumor growth, recurrence and metastasis is needed to identify a novel diagnostic/prognostic biomarker for cervical cancer, which is critical for cervical cancer risk screening. In addition, it is also necessary to identify HLA-G-driven immune mechanisms involved in the interactions between host and virus to explore novel immunotherapy strategies that target HLA-G/immunoglobulin-like transcript (ILT) immune checkpoints.
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Affiliation(s)
- Hui-Hui Xu
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Wei-Hua Yan
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Aifen Lin
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
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23
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Ben Yahia H, Boujelbene N, Babay W, Ben Safta I, Dhouioui S, Zemni I, Ali Ayadi M, Charfi L, Ouzari HI, Rebmann V, Rizzo R, Mrad K, Driss M, Zidi I. Expression analysis of immune-regulatory molecules HLA-G, HLA-E and IDO in endometrial cancer. Hum Immunol 2020; 81:305-313. [PMID: 32273131 DOI: 10.1016/j.humimm.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 03/01/2020] [Accepted: 03/26/2020] [Indexed: 11/17/2022]
Abstract
HLA-G has been widely implicated in advanced cancers through different pathways of immunosuppression allowing tumor escape. Contrarily, HLA-E has a controversial role in the tumor escape from the immune system. IDO catabolic enzyme is known to be up-regulated in many tumors types allowing their immune escape. Based on these considerations, we investigated the expression of HLA-G, HLA-E and IDO molecules in endometrial cancer (EC) and their association with prognostic clinicopathologic parameters. Their expression were checked in tumoral and adjacent endometrial tissues. Both HLA-G and IDO immunostaining were significantly increased in EC tissues compared to normal residual endometrial glands (Mann Whitney U-test, p = 0.0001 and p = 0,020 respectively). However, HLA-E was highly expressed in tumoral tissues as well as in normal residual endometrial glands (respectively, 100% and 81.8%). Increased HLA-G expression levels were observed in high histological grade (grade 3), and in the non-endometrioid type 2 EC. Unexpectedly, patients with IDO Low expression had significantly impaired overall survival compared to patients with IDO High (log-rank p = 0.021). Conversely, HLA-E low expression was associated to an improved overall survival EC (log-rank p = 0.004). We concluded that, HLA-G and IDO are highly expressed in EC compared to adjacent normal endometrial tissues, that might be interesting for the EC outcome.
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Affiliation(s)
- Hamza Ben Yahia
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Nadia Boujelbene
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia; Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Wafa Babay
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Inès Ben Safta
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Sabrine Dhouioui
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Inès Zemni
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Mohamed Ali Ayadi
- Surgical Oncology Department, Salah Azaiz Institute of Cancer, Tunis, Tunisia
| | - Lamia Charfi
- Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Hadda Imene Ouzari
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia
| | - Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, Virchowstr. 179, 45147 Essen, Germany
| | - Roberta Rizzo
- Department of Experimental and Diagnostic Medicine, Section Microbiology, University of Ferrara, Ferrara, Italy
| | - Karima Mrad
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia; Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Maha Driss
- Department of Anatomopathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Inès Zidi
- Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, University Tunis El Manar, Tunis, Tunisia.
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24
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Al-Khunaizi NR, Tabbara KS, Farid EM. Is there a role for HLA-G in the induction of regulatory T cells during the maintenance of a healthy pregnancy? Am J Reprod Immunol 2020; 84:e13259. [PMID: 32352606 DOI: 10.1111/aji.13259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/02/2020] [Accepted: 04/23/2020] [Indexed: 11/27/2022] Open
Abstract
PROBLEM Pregnancy remains an immune challenge for the uterus that has to adapt to a semi-allogeneic fetus using various regulatory mechanisms. Both HLA-G and regulatory T cells (CD4+ CD25+ FOXP3+ Tregs ) are upregulated in successful pregnancy, but not in abortion. It is unclear if HLA-G plays a role in the upregulation of regulatory cells. METHOD OF STUDY We measured the level of both sHLA-G and Treg cells in the blood of healthy pregnant multigravida, unexplained recurrent spontaneous abortions (URSA) and healthy non-pregnant and nulliparous females. We cultured peripheral blood lymphocytes of healthy non-pregnant multigravida females who never had an abortion with lymphocytes of their partners at ratio of 1:1, with and without sHLA-G to detect changes in number of Treg cells, or relevant cytokines. RESULTS Soluble HLA-G concentrations and Treg cells percentage were significantly lower in women with URSA as compared to healthy pregnant multigravida women and were comparable to healthy non-pregnant nulliparous women. Percentage of Tregs increased between zero time and mixed lymphocyte cultures (MLC) in both cultures with and without recombinant sHLA-G but no significant difference between the two cultures. When stimulated with sHLA-G the mean extracellular IL-10 concentration was unchanged, while the mean INF-γ concentration was slightly higher with no significant difference. Intracellular TGF-β was higher in CD4+ cells after incubation with sHLA-G. CONCLUSION The results of this study are consistent with previous studies on the role of sHLA-G and Treg cells in inducing immune-tolerance in pregnancy. The results also suggest a possible role for HLA-G in the enrichment of Treg cells.
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Affiliation(s)
- Nada R Al-Khunaizi
- Molecular Medicine Program, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Khaled S Tabbara
- Molecular Medicine Program, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.,Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Eman M Farid
- Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.,Senior Consultant Immunologist - Pathology Department, Salmaniya Medical Complex, Manama, Bahrain
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25
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Ajith A, Portik-Dobos V, Horuzsko DD, Kapoor R, Mulloy LL, Horuzsko A. HLA-G and humanized mouse models as a novel therapeutic approach in transplantation. Hum Immunol 2020; 81:178-185. [PMID: 32093884 DOI: 10.1016/j.humimm.2020.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 02/15/2020] [Accepted: 02/17/2020] [Indexed: 01/12/2023]
Abstract
HLA-G is a nonclassical MHC-Class I molecule whose expression, along the feto-maternal barrier contributes towards tolerance of the semiallogeneic fetus during pregnancy. In light of its inhibitory properties, recent research has established HLA-G involvement in mechanisms responsible for directing allogeneic immune responses towards tolerance during allogeneic situations such as organ transplantation. Here, we critically review the data supporting the tolerogenic role of HLA-G in organ transplantation, the various factors influencing its expression, and the introduction of novel humanized mouse models that are one of the best approaches to assess the utility of HLA-G as a therapeutic tool in organ transplantation.
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Affiliation(s)
- Ashwin Ajith
- Georgia Cancer Canter, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Vera Portik-Dobos
- Georgia Cancer Canter, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Daniel D Horuzsko
- Philadelphia College of Osteopathic Medicine South Georgia, Moultrie, GA, USA
| | - Rajan Kapoor
- Division of Nephrology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Laura L Mulloy
- Division of Nephrology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Anatolij Horuzsko
- Georgia Cancer Canter, Medical College of Georgia, Augusta University, Augusta, GA, USA.
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Human Hepatocytes and Differentiated Adult-Derived Human Liver Stem/Progenitor Cells Display In Vitro Immunosuppressive Properties Mediated, at Least in Part, through the Nonclassical HLA Class I Molecule HLA-G. J Immunol Res 2019; 2019:8250584. [PMID: 31612154 PMCID: PMC6757295 DOI: 10.1155/2019/8250584] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 08/08/2019] [Indexed: 12/25/2022] Open
Abstract
One of the main challenges in liver cell therapy (LCT) is the induction of a tolerogenic microenvironment to promote graft acceptance in the recipient. Little is known about the immunomodulatory potential of the hepatic cells used in liver cell therapy. In this work, we wanted to evaluate the immunosuppressive properties of human hepatocytes and adult-derived human liver stem/progenitor cells (ADHLSCs), as well as the potential involvement of the immunomodulatory molecule HLA-G. We demonstrated that both cell types were capable of inhibiting the proliferative response of PBMCs to an allogenic stimulus and that the immune inhibitory potential of ADHLSCs, although lower than that of hepatocytes, increased after hepatogenic differentiation. We demonstrated that liver cells express HLA-G and that the immune inhibition pattern was clearly associated to its expression. Interestingly, HLA-G expression increased after the third step of differentiation, wherein oncostatin M (OSM) was added. A 48 hr treatment with OSM was sufficient to induce HLA-G expression in ADHLSCs and result in immune inhibition. Surprisingly, blocking HLA-G partially reversed the immune inhibition mediated by hepatocytes and differentiated ADHLSCs, but not that of undifferentiated ADHLSCs, suggesting that additional immune inhibitory mechanisms may be used by these cells. In conclusion, we demonstrated that both hepatocytes and ADHLSCs present immunomodulatory properties mediated, at least in part, through HLA-G, which can be upregulated following hepatogenic differentiation or liver cell pretreatment with OSM. These observations open up new perspectives for the induction of tolerance following LCT and for potential therapeutic applications of these liver cells.
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27
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Dumont C, Jacquier A, Verine J, Noel F, Goujon A, Wu CL, Hung TM, Desgrandchamps F, Culine S, Carosella ED, Rouas-Freiss N, LeMaoult J. CD8 +PD-1 -ILT2 + T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune-Checkpoint HLA-G. Cancer Immunol Res 2019; 7:1619-1632. [PMID: 31451484 DOI: 10.1158/2326-6066.cir-18-0764] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 04/25/2019] [Accepted: 08/20/2019] [Indexed: 11/16/2022]
Abstract
Only some cancer patients respond to the immune-checkpoint inhibitors being used in the clinic, and other therapeutic targets are sought. Here, we investigated the HLA-G/ILT2 checkpoint in clear-cell renal-cell carcinoma (ccRCC) patients and focused on tumor-infiltrating CD8+ T lymphocytes (TIL) expressing the HLA-G receptor ILT2. Using transcriptomics and flow cytometry, we characterized both peripheral blood and tumor-infiltrating CD8+ILT2+ T cells from cancer patients as late-differentiated CD27-CD28-CD57+ cytotoxic effectors. We observed a clear dichotomy between CD8+ILT2+ and CD8+PD-1+ TIL subsets. These subsets, which were sometimes present at comparable frequencies in TIL populations, barely overlapped phenotypically and were distinguished by expression of exclusive sets of surface molecules that included checkpoint molecules and activating and inhibitory receptors. CD8+ILT2+ TILs displayed a more mature phenotype and higher expression of cytotoxic molecules. In ex vivo functional experiments with both peripheral blood T cells and TILs, CD8+ILT2+ T cells displayed significantly higher cytotoxicity and IFNγ production than their ILT2- (peripheral blood mononuclear cells, PBMC) and PD-1+ (TILs) counterparts. HLA-G expression by target cells specifically inhibited CD8+ILT2+ T-cell cytotoxicity, but not that of their CD8+ILT2- (PBMC) or CD8+PD-1+ (TIL) counterparts, an effect counteracted by blocking the HLA-G/ILT2 interaction. CD8+ILT2+ TILs may therefore constitute an untapped reservoir of fully differentiated cytotoxic T cells within the tumor microenvironment, independent of the PD1+ TILs targeted by immune therapies, and specifically inhibited by HLA-G. These results emphasize the potential of therapeutically targeting the HLA-G/ILT2 checkpoint in HLA-G+ tumors, either concomitantly with anti-PD-1/PD-L1 or in cases of nonresponsiveness to anti-PD-1/PD-L1.
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Affiliation(s)
- Clement Dumont
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France.,Department of Medical Oncology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Alix Jacquier
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France
| | - Jerome Verine
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France.,Department of Pathology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France and Paris-Diderot University, Paris, France
| | - Floriane Noel
- Institut Curie, PSL Research University, France and INSERM, UMR 932, Paris, France and Université Paris Sud, Université Paris-Saclay, Orsay, France
| | - Annabelle Goujon
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France.,Department of Urology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Ching-Lien Wu
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France
| | - Tzu-Min Hung
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,National Taiwan University Hospital, Taipei City, Taiwan, Republic of China; University of Taipei and E-Da Hospital/I-Shou University, Yan-Chau Shiang, Kaohsiung County, Taiwan, Republic of China
| | - François Desgrandchamps
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France.,Department of Urology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Stephane Culine
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France.,Department of Medical Oncology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Edgardo D Carosella
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France
| | - Nathalie Rouas-Freiss
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France.,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France
| | - Joel LeMaoult
- Hemato-Immunology Research Department, CEA-DRF, Saint-Louis Hospital, Paris, France. .,Paris-Diderot University, Sorbonne-Paris-Cité, Paris, France
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28
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Rezaei F, Zareei N, Razmi N, Nikeghbalian S, Azarpira N. Genetic Polymorphism of HLA-G 14-bp Insertion/Deletion in Pancreas Transplant Recipients and Its Association With Type 1 Diabetes Mellitus. EXP CLIN TRANSPLANT 2019; 19:154-159. [PMID: 30702046 DOI: 10.6002/ect.2018.0162] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Human leukocyte antigen-G is an immuno-modulatory factor that affects acute allograft rejection and autoimmune diseases such as type 1 diabetes mellitus. In this study, possible associations between human leukocyte antigen-G 14-bp insertion/deletion polymorphism and acute pancreas rejection were investigated. MATERIALS AND METHODS Human leukocyte antigen-G genotyping was assessed in 102 Iranian pancreas transplant recipients (including 41 with acute rejection and 61 with nonacute rejection). Results were compared with 100 individuals in a normal control group. RESULTS No significant differences in genotype frequencies of human leukocyte antigen-G 14-bp insertion / deletion were observed in recipients who had acute rejection episodes. On the other hand, the insertion / insertion genotype was a risk factor for susceptibility to type 1 diabetes mellitus (odds ratio = 3.82, 95% confidence interval, 1.37- 11.22; P = .005). CONCLUSIONS Our results provided evidence revealing that the human leukocyte antigen-G insertion / insertion genotype might be involved in the pathogenesis of type 1 diabetes mellitus.
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Affiliation(s)
- Firoozeh Rezaei
- From the Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; and the Department of Biochemistry, Faculty of Basic Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran
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29
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Janssen M, Thaiss F, Nashan B, Koch M, Thude H. Donor derived HLA-G polymorphisms have a significant impact on acute rejection in kidney transplantation. Hum Immunol 2019; 80:176-183. [PMID: 30610894 DOI: 10.1016/j.humimm.2018.12.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 12/04/2018] [Accepted: 12/31/2018] [Indexed: 12/22/2022]
Abstract
Human leucocyte antigen G (HLA-G) is a non-classical HLA-class I antigen that exerts immunoregulatory functions. The polymorphisms 14-base pair (bp) insertion/deletion (ins/del) (rs1704) and +3142C > G (rs1063320) could modify the expression level of HLA-G. We genotyped 175 kidney recipients (41 with acute rejection and 134 without rejection) and additionally the corresponding donors for both polymorphisms in order to assess their impact on acute rejections one year after transplantation. In addition, we analyzed soluble HLA-G (sHLA-G) levels in sera of 32 living kidney donors and compared the sHLA-G levels in terms of the present genotype. In kidney transplant recipients we did not observe an impact of the 14-bp ins/ins and the +3142GG genotypes on acute rejection. In contrast, we found a higher frequency of these genotypes in the donors of the no-rejection collective compared to the rejection collective (4.9% vs. 24.6%; p = 0.010; 9.8% vs. 31.3%; p = 0.006). Soluble HLA-G levels were highest in healthy kidney donors homozygous for the 14-bp insertion. We conclude that the HLA-G polymorphisms of the donor are of importance for susceptibility of acute rejection in kidney transplantation. We suggest that the 14-bp ins/ins and the +3142GG genotypes are protective against kidney transplant rejection.
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Affiliation(s)
- Maike Janssen
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany; University Hospital Heidelberg, Department for Hematology, Oncology and Rheumatology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
| | - Friedrich Thaiss
- University Medical Center Hamburg-Eppendorf, Center for Internal Medicine, Martinistraße 52, 20246 Hamburg, Germany
| | - Björn Nashan
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany; University of Science and Technology, Hefei, Anhui, China
| | - Martina Koch
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany; University Medical Center of the Johannes Gutenberg University Mainz, Department of General, Visceral, and Abdominal Surgery, Langenbeckstraße 1, 55131 Mainz, Germany
| | - Hansjörg Thude
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany
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30
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Mirzakhani M, Shahbazi M, Oliaei F, Mohammadnia-Afrouzi M. Immunological biomarkers of tolerance in human kidney transplantation: An updated literature review. J Cell Physiol 2018; 234:5762-5774. [PMID: 30362556 DOI: 10.1002/jcp.27480] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 09/06/2018] [Indexed: 12/11/2022]
Abstract
The half-life of transplanted kidneys is <10 years. Acute or chronic rejections have a negative impact on transplant outcome. Therefore, achieving to allograft tolerance for improving long-term transplant outcome is a desirable goal of transplantation field. In contrast, there are evidence that distinct immunological characteristics lead to tolerance in some transplant recipients. In contrast, the main reason for allograft loss is immunological responses. Various immune cells including T cells, B cells, dendritic cells, macrophages, natural killer, and myeloid-derived suppressor cells damage graft tissue and, thereby, graft loss happens. Therefore, being armed with the comprehensive knowledge about either preimmunological or postimmunological characteristics of renal transplant patients may help us to achieve an operational tolerance. In the present study, we are going to review and discuss immunological characteristics of renal transplant recipients with rejection and compare them with tolerant subjects.
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Affiliation(s)
- Mohammad Mirzakhani
- Student Research Committee, School of Medicine, Babol University of Medical Sciences, Babol, Iran.,Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mehdi Shahbazi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Farshid Oliaei
- Kidney Transplantation Center, Shahid Beheshti Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Mousa Mohammadnia-Afrouzi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Immunoregulation Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Immunology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
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31
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Elimination of CD4 lowHLA-G + T cells overcomes castration-resistance in prostate cancer therapy. Cell Res 2018; 28:1103-1117. [PMID: 30297869 DOI: 10.1038/s41422-018-0089-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 07/12/2018] [Accepted: 08/26/2018] [Indexed: 12/22/2022] Open
Abstract
Androgen deprivation therapy (ADT) is a main treatment for prostate cancer (PCa) but the disease often recurs and becomes castration-resistant in nearly all patients. Recent data implicate the involvement of immune cells in the development of this castration-resistant prostate cancer (CRPC). In particular, T cells have been found to be expanded in both PCa patients and mouse models shortly after androgen deprivation. However, whether or which of the T cell subtypes play an important role during the development of CRPC is unknown. Here we identified a novel population of CD4lowHLA-G+ T cells that undergo significant expansion in PCa patients after ADT. In mouse PCa models, a similar CD4low T cell population expands during the early stages of CRPC onset. These cells are identified as IL-4-expressing TH17 cells, and are shown to be associated with CRPC onset in patients and essential for the development of CRPC in mouse models. Mechanistically, CD4lowHLA-G+ T cells drive androgen-independent growth of prostate cancer cells by modulating the activity and migration of CD11blowF4/80hi macrophages. Furthermore, following androgen deprivation, elevated PGE2-EP2 signaling inhibited the expression of CD4 in thymocytes, and subsequently induced the polarization of CD4low naïve T cells towards the IL-4-expressing TH17 phenotype via up-regulation of IL23R. Therapeutically, inactivating PGE2 signaling with celecoxib at a time when CD4lowHLA-G+ T cells appeared, but not immediately following androgen deprivation, dramatically suppressed the onset of CRPC. Collectively, our results indicate that an unusual population of CD4lowHLA-G+ T cells is essential for the development of CRPC and point to a new therapeutic avenue of combining ADT with PGE2 inhibition for the treatment of prostate cancer.
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32
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Luetragoon T, Rutqvist LE, Tangvarasittichai O, Andersson BÅ, Löfgren S, Usuwanthim K, Lewin NL. Interaction among smoking status, single nucleotide polymorphisms and markers of systemic inflammation in healthy individuals. Immunology 2018; 154:98-103. [PMID: 29140561 DOI: 10.1111/imm.12864] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/26/2017] [Accepted: 11/04/2017] [Indexed: 12/24/2022] Open
Abstract
Cigarette smoke contains toxic and carcinogenic substances that contribute to the development of cancer and various diseases. Genetic variation might be important, because not all smokers develop smoking-related disease. The current study addressed the possible interactions among selected single nucleotide polymorphisms (SNPs) in genes related to systemic inflammation, smoking status, the levels of circulating immune response cells and plasma biomarkers of systemic inflammation. Sixty-four healthy blood donors were recruited, 31 of whom were current smokers and 33 were never-users of tobacco products, references. Compared to references, the smokers showed significantly increased levels of circulating total white blood cells, lymphocytes, monocytes, neutrophils, basophils and C-reactive protein (CRP). Smokers also more frequently exhibited circulating cell phenotypes that are associated with an immunocompromised state: CD8dim cells in the lymphocyte group, CD13+ CD11+ , CD13+ CD14+ , CD13+ CD56+ cells in the monocyte group and CD13+ CD11+ , CD13+ CD56+ cells in the neutrophil group. We observed an interaction among SNPs, smoking status and some of the studied biomarkers. The average plasma CRP level was significantly higher among the smokers, with the highest level found among those with the CRP rs1800947 CC genotype. Additionally, an increased CD8+ GZB+ cells in the CD8dim group were found among smokers with the GZB rs8192917 AA genotype. Thus, smoking appears to be associated with systemic inflammation and increased levels of circulating immunosuppressive cells. The extent of these effects was associated with SNPs among the smokers. This observation may contribute to a better understanding of the genetic susceptibility of smoking-related disease and the variations observed in clinical outcomes.
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Affiliation(s)
- Thitiya Luetragoon
- Department of Medical Technology, Naresuan University, Phitsanulok, Thailand.,Department of Laboratory Medicine, Ryhov Hospital, Jönköping, Sweden.,Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Lars E Rutqvist
- Scientific Affairs Group, Swedish Match AB, Stockholm, Sweden
| | | | - Bengt-Åke Andersson
- Department of Laboratory Medicine, Ryhov Hospital, Jönköping, Sweden.,Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Sture Löfgren
- Department of Laboratory Medicine, Ryhov Hospital, Jönköping, Sweden
| | - Kanchana Usuwanthim
- Department of Medical Technology, Naresuan University, Phitsanulok, Thailand
| | - Nongnit L Lewin
- Department of Laboratory Medicine, Ryhov Hospital, Jönköping, Sweden.,Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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33
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Twardziok M, Schröder PC, Krusche J, Casaca VI, Illi S, Böck A, Loss GJ, Kabesch M, Toncheva AA, Roduit C, Depner M, Genuneit J, Renz H, Roponen M, Weber J, Braun-Fahrländer C, Riedler J, Lauener R, Vuitton DA, Dalphin JC, Pekkanen J, von Mutius E, Schaub B, Hyvärinen A, Karvonen AM, Kirjavainen PV, Remes S, Kaulek V, Dalphin ML, Ege M, Pfefferle PI, Doekes G. Asthmatic farm children show increased CD3 +CD8 low T-cells compared to non-asthmatic farm children. Clin Immunol 2017; 183:285-292. [PMID: 28917722 DOI: 10.1016/j.clim.2017.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/28/2017] [Accepted: 09/12/2017] [Indexed: 11/15/2022]
Affiliation(s)
- Monika Twardziok
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Paul C Schröder
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Johanna Krusche
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany; Member of German Center for Lung Research, DZL, LMU Munich, Germany
| | - Vera I Casaca
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Sabina Illi
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Andreas Böck
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Georg J Loss
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany; University of California, San Diego, School of Medicine, Department of Pediatrics, CA, USA
| | - Michael Kabesch
- Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany
| | - Antoaneta A Toncheva
- Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany
| | - Caroline Roduit
- Zurich University Children's Hospital, Zurich, Switzerland; Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland and Christine Kühne-Center for Allergy Research and Education, St. Gallen, Switzerland
| | - Martin Depner
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany
| | - Jon Genuneit
- Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
| | - Harald Renz
- Institute of Laboratory Medicine, Philipps University Marburg, Marburg, Germany; Member of German Center for Lung Research, DZL, LMU Munich, Germany
| | - Marjut Roponen
- Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio, Finland
| | - Juliane Weber
- Bavarian Health and Food Safety Authority, Oberschleißheim, Germany
| | | | | | - Roger Lauener
- Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland and Christine Kühne-Center for Allergy Research and Education, St. Gallen, Switzerland
| | | | | | - Juha Pekkanen
- Department of Public health, University of Helsinki, Helsinki, Finland; Department of Health Security, National Institute for Health and Welfare, Kuopio, Finland
| | - Erika von Mutius
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany; Member of German Center for Lung Research, DZL, LMU Munich, Germany
| | - Bianca Schaub
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany; Member of German Center for Lung Research, DZL, LMU Munich, Germany.
| | | | - Anne Hyvärinen
- Department of Health Security, National Institute for Health and Welfare, Kuopio, Finland
| | - Anne M Karvonen
- Department of Health Security, National Institute for Health and Welfare, Kuopio, Finland
| | - Pirkka V Kirjavainen
- Department of Health Security, National Institute for Health and Welfare, Kuopio, Finland
| | - Sami Remes
- Kuopio University Hospital, Department of Paediatrics, Kuopio, Finland
| | - Vincent Kaulek
- University Hospital of Besançon, University of Franche-Comté, Besançon, France
| | - Marie-Laure Dalphin
- University Hospital of Besançon, University of Franche-Comté, Besançon, France
| | - Markus Ege
- Dr. von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany; Member of German Center for Lung Research, DZL, LMU Munich, Germany
| | - Petra I Pfefferle
- Institute of Laboratory Medicine, Philipps University Marburg, Marburg, Germany; Member of German Center for Lung Research, DZL, LMU Munich, Germany
| | - Gert Doekes
- Utrecht University, Institut for Risk Assessment Sciences (IRAS), Devision of Environmental Epidemiology, Utrecht, Netherlands
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34
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Melsted WN, Johansen LL, Lock-Andersen J, Behrendt N, Eriksen JO, Bzorek M, Scheike T, Hviid TVF. HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients. Clin Immunol 2017; 183:191-197. [PMID: 28882620 DOI: 10.1016/j.clim.2017.09.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 08/26/2017] [Accepted: 09/01/2017] [Indexed: 12/27/2022]
Abstract
HLA class Ia (HLA-ABC) and HLA class Ib (HLA-E, -F and -G) molecules and FOXP3+ tumor-infiltrating lymphocytes (TILs) are often reported as relevant factors of tumor immune regulation. We investigated their expression as prognostic factors in 200 patients with primary cutaneous melanoma (PCM). In our cohort, patients with tumors showing upregulation of HLA-ABC molecules had significantly thicker tumors (32% vs 7%, P<0.001), frequent ulceration (20% vs 6%, P=0.007) and frequent nodular melanomas (20% vs 4%, P=0.001). Additionally, high expression of HLA-G in the tumor was a sign of bad prognosis for the patients, being associated with thick tumors (30% vs 12%, P=0.017), ulceration (24% vs 5%, P<0.001) and positive sentinel node (13% vs 6%, P=0.015). HLA-E, HLA-F and FOXP3+ TILs were not indicative of the prognosis in PCM. High HLA-ABC and HLA-G were associated with tumor aggressiveness and could be relevant predictive markers for effective immunotherapy of melanoma tumors.
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Affiliation(s)
- Wenna Nascimento Melsted
- Centre for Immune Regulation and Reproductive Immunology (CIRRI), Department of Clinical Biochemistry, Zealand University Hospital, DK-4000 Roskilde, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Lasse Lindholm Johansen
- Centre for Immune Regulation and Reproductive Immunology (CIRRI), Department of Clinical Biochemistry, Zealand University Hospital, DK-4000 Roskilde, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Jørgen Lock-Andersen
- Department of Plastic Surgery, Zealand University Hospital, Roskilde, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Nille Behrendt
- Department of Pathology, Zealand University Hospital, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Jens Ole Eriksen
- Department of Pathology, Zealand University Hospital, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Michael Bzorek
- Department of Pathology, Zealand University Hospital, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| | - Thomas Scheike
- Department of Biostatistics, University of Copenhagen, Denmark
| | - Thomas Vauvert F Hviid
- Centre for Immune Regulation and Reproductive Immunology (CIRRI), Department of Clinical Biochemistry, Zealand University Hospital, DK-4000 Roskilde, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark.
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35
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Rouas-Freiss N, LeMaoult J, Verine J, Tronik-Le Roux D, Culine S, Hennequin C, Desgrandchamps F, Carosella ED. Intratumor heterogeneity of immune checkpoints in primary renal cell cancer: Focus on HLA-G/ILT2/ILT4. Oncoimmunology 2017; 6:e1342023. [PMID: 28932645 DOI: 10.1080/2162402x.2017.1342023] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 05/22/2017] [Accepted: 06/07/2017] [Indexed: 02/08/2023] Open
Abstract
The establishment and maintenance of anti-tumor immune responses are the objectives of cancer immunotherapy. Despite recent promising advances, the effectiveness of these approaches has been limited by the multiple immunosuppressive mechanisms developed by tumors (checkpoint). The aim of the present study was to demonstrate intratumor heterogeneity at the levels of immune escape strategies and tumor-host relationships. We focused on well-known checkpoints such as PD1/PDL1 and on a new checkpoint involving HLA-G and its receptors ILT2/ILT4. A prospective study was performed on 19 renal-cell carcinoma patients that were included during hospitalization for surgical tumor resection. Different areas of the tumor were collected for each patient and subjected to both immunohistochemical and flow cytometry analysis. Immune cells from peripheral blood were concomitantly analyzed for each patient. Our results show the heterogeneous expression of PD1/PDL1 and HLA-G/ILT in the various areas of the same tumor. Intratumor heterogeneity was found both at tumor cell and infiltrating immune cell levels. From a clinical point of view, this work highlights the functional redundancies of checkpoints and the need to adapt personalized poly-immunotherapy.
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Affiliation(s)
- Nathalie Rouas-Freiss
- CEA, Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France.,Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France
| | - Joel LeMaoult
- CEA, Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France.,Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France
| | - Jérôme Verine
- CEA, Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France.,Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France.,Service d'Anatomo-Pathologie, AP-HP, Hopital Saint-Louis, Paris, France
| | - Diana Tronik-Le Roux
- CEA, Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France.,Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France
| | - Stéphane Culine
- CEA, Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France.,Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France.,Service d'Oncologie Médicale, AP-HP, Hopital Saint-Louis, Paris, France
| | - Christophe Hennequin
- CEA, Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France.,Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France.,Service de Radiothérapie, AP-HP, Hopital Saint-Louis, Paris, France
| | - François Desgrandchamps
- CEA, Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France.,Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France.,Service d'Urologie, AP-HP, Hopital Saint-Louis, Paris, France
| | - Edgardo D Carosella
- CEA, Direction de la Recherche Fondamentale (DRF), Service de Recherche en Hemato-Immunologie (SRHI), Paris, France.,Universite Paris Diderot, Sorbonne Paris Cite, IUH, Hopital Saint-Louis, UMR_E5, Paris, France
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36
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Okushi Y, Okino K, Mukai K, Matsui Y, Hayashi N, Fujimoto K, Adachi H, Yamaya H, Yokoyama H. Circulating and renal expression of HLA-G prevented chronic renal allograft dysfunction in Japanese recipients. Clin Exp Nephrol 2017; 21:932-940. [DOI: 10.1007/s10157-016-1378-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 12/05/2016] [Indexed: 11/28/2022]
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Ghaebi M, Nouri M, Ghasemzadeh A, Farzadi L, Jadidi-Niaragh F, Ahmadi M, Yousefi M. Immune regulatory network in successful pregnancy and reproductive failures. Biomed Pharmacother 2017; 88:61-73. [PMID: 28095355 DOI: 10.1016/j.biopha.2017.01.016] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2016] [Revised: 12/27/2016] [Accepted: 01/02/2017] [Indexed: 12/23/2022] Open
Abstract
Maternal immune system must tolerate semiallogenic fetus to establish and maintain a successful pregnancy. Despite the existence of several strategies of trophoblast to avoid recognition by maternal leukocytes, maternal immune system may react against paternal alloantigenes. Leukocytes are important components in decidua. Not only T helper (Th)1/Th2 balance, but also regulatory T (Treg) cells play an important role in pregnancy. Although the frequency of Tregs is elevated during normal pregnancies, their frequency and function are reduced in reproductive defects such as recurrent miscarriage and preeclampsia. Tregs are not the sole population of suppressive cells in the decidua. It has recently been shown that regulatory B10 (Breg) cells participate in pregnancy through secretion of IL-10 cytokine. Myeloid derived suppressor cells (MDSCs) are immature developing precursors of innate myeloid cells that are increased in pregnant women, implying their possible function in pregnancy. Natural killer T (NKT) cells are also detected in mouse and human decidua. They can also affect the fetomaternal tolerance. In this review, we will discuss on the role of different immune regulatory cells including Treg, γd T cell, Breg, MDSC, and NKT cells in pregnancy outcome.
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Affiliation(s)
- Mahnaz Ghaebi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Nouri
- Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliyeh Ghasemzadeh
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Laya Farzadi
- Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Ahmadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; 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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38
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Thude H, Janssen M, Sterneck M, Nashan B, Koch M. 14-bp ins/del polymorphism and +3142C>G SNP of the HLA-G gene have a significant impact on acute rejection after liver transplantation. Hum Immunol 2016; 77:1159-1165. [PMID: 27664842 DOI: 10.1016/j.humimm.2016.09.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 09/18/2016] [Accepted: 09/20/2016] [Indexed: 01/01/2023]
Abstract
Expression of human leukocyte antigen G (HLA-G) has been associated with increased graft survival and decreased rejection episodes. It has been described that the HLA-G 14-base pair (bp) insertion/deletion (ins/del) (rs66554220) and +3142C>G (rs1063320) gene polymorphisms modify the expression level of HLA-G. The aim of the study was to investigate whether these HLA-G polymorphisms have an impact on acute rejection after liver transplantation. In total, 146 liver transplant recipients (57 with acute rejection and 89 without acute rejection) and 99 corresponding liver donors were genotyped for both polymorphisms. In liver transplantation the 14-bp ins/ins and the +3142GG genotypes are more frequent in recipients without rejection compared to recipients with rejection (3.5% vs. 31.5%, p=<0.001; 12.3% vs. 41.6%, p=<0.001) demonstrating an association with protection from acute rejection. In contrast, in liver donors we could not reveal an association. We conclude that 14-bp ins/ins and +3142GG genotypes of HLA-G in liver transplant recipients are of importance for prediction of acute rejection after liver transplantation. Thus genotyping of liver recipients for both polymorphisms might be useful to stratify liver transplant recipients according to the risk of acute liver transplant rejection.
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Affiliation(s)
- Hansjörg Thude
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany.
| | - Maike Janssen
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany
| | - Martina Sterneck
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany
| | - Björn Nashan
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany
| | - Martina Koch
- University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany
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Takahashi A, Kuroki K, Okabe Y, Kasai Y, Matsumoto N, Yamada C, Takai T, Ose T, Kon S, Matsuda T, Maenaka K. The immunosuppressive effect of domain-deleted dimer of HLA-G2 isoform in collagen-induced arthritis mice. Hum Immunol 2016; 77:754-9. [DOI: 10.1016/j.humimm.2016.01.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 01/11/2016] [Indexed: 11/26/2022]
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40
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Nardi FDS, König L, Wagner B, Giebel B, Santos Manvailer LF, Rebmann V. Soluble monomers, dimers and HLA-G-expressing extracellular vesicles: the three dimensions of structural complexity to use HLA-G as a clinical biomarker. HLA 2016; 88:77-86. [PMID: 27440734 DOI: 10.1111/tan.12844] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 06/29/2016] [Indexed: 12/11/2022]
Abstract
The HLA-G molecule belongs to the family of nonclassical human leukocyte antigen (HLA) class I. At variance to classical HLA class I, HLA-G displays (i) a low number of nucleotide variations within the coding region, (ii) a high structural diversity, (iii) a restricted peptide repertoire, (iv) a limited tissue distribution and (v) strong immune-suppressive properties. The physiological HLA-G surface expression is restricted to the maternal-fetal interface and to immune-privileged adult tissues. Soluble forms of HLA-G (sHLA-G) are detectable in various body fluids. Cellular activation and pathological processes are associated with an aberrant or a neo-expression of HLA-G/sHLA-G. Functionally, HLA-G and its secreted forms are considered to be key players in the induction of short- and long-term tolerance. Thus, its unique expression profile and tolerance-inducing functions render HLA-G/sHLA-G an attractive biomarker to monitor the systemic health/disease status and disease activity/progression for clinical approaches in disease management and treatments. Here, we place emphasis on (i) the current status of the tolerance-inducing functions by HLA-G/sHLA-G, (ii) the current complexity to implement this molecule as a meaningful clinical biomarker regarding the three dimensions of structural diversity (monomers, dimers and HLA-G-expressing extracellular vesicles) with its functional implications, and (iii) novel and future approaches to detect and quantify sHLA-G structures and functions.
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Affiliation(s)
- F da Silva Nardi
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany.,Laboratory of Immunogenetics and Histocompatibility (LIGH), Federal University of Paraná, Genetics Department, Curitiba, Brazil.,Ministry of Education of Brazil, Capes Foundation, Brasília, Brazil
| | - L König
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany.,Department of Gynecology and Obstetrics, University of Duisburg-Essen, Essen, Germany
| | - B Wagner
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
| | - B Giebel
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
| | - L F Santos Manvailer
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany.,Ministry of Education of Brazil, Capes Foundation, Brasília, Brazil
| | - V Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany
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41
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Rebmann V, König L, Nardi FDS, Wagner B, Manvailer LFS, Horn PA. The Potential of HLA-G-Bearing Extracellular Vesicles as a Future Element in HLA-G Immune Biology. Front Immunol 2016; 7:173. [PMID: 27199995 PMCID: PMC4854879 DOI: 10.3389/fimmu.2016.00173] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 04/19/2016] [Indexed: 12/21/2022] Open
Abstract
The HLA-G molecule is a member of the non-classical HLA class I family. Its surface expression is physiologically restricted to the maternal–fetal interface and to immune privileged adult tissues. Despite the restricted tissue expression, HLA-G is detectable in body fluids as secreted soluble molecules. A unique feature of HLA-G is the structural diversity as surface expressed and as secreted molecules. Secreted HLA-G can be found in various body fluids either as free soluble HLA-G or as part of extracellular vesicles (EVs), which are composed of various antigens/ligands/receptors, bioactive lipids, cytokines, growth factors, and genetic information, such as mRNA and microRNA. Functionally, HLA-G and its secreted forms are considered to play a crucial role in the network of immune-regulatory tolerance mechanisms, preferentially interacting with the cognate inhibitory receptors LILRB1 and LILRB2. The HLA-G mediated tolerance is described in processes of pregnancy, inflammation, and cancer. However, almost all functional and clinical implications of HLA-G in vivo and in vitro have been established based on simple single ligand/receptor interactions at the cell surface, whereas HLA-G-bearing EVs were in minor research focus. Indeed, cytotrophoblast cells, mesenchymal stem cells, and cancer cells were recently described to secrete HLA-G-bearing EVs, displaying immunosuppressive effects and modulating the tumor microenvironment. However, numerous functional and clinical open questions persist. Here, we (i) introduce basic aspects of EVs biology, (ii) summarize the functional knowledge, clinical implications and open questions of HLA-G-bearing EVs, and (iii) discuss HLA-G-bearing EVs as a future element in HLA-G biology.
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Affiliation(s)
- Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen , Essen , Germany
| | - Lisa König
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany; Department of Gynecology and Obstetrics, Essen, Germany
| | - Fabiola da Silva Nardi
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany; Laboratory of Immunogenetics and Histocompatibility (LIGH), Federal University of Paraná Genetics Department, Curitiba, Paraná, Brazil; CAPES Foundation, Ministry of Education of Brazil, Brasília, Federal District, Brazil
| | - Bettina Wagner
- Institute for Transfusion Medicine, University Hospital Essen , Essen , Germany
| | - Luis Felipe Santos Manvailer
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany; CAPES Foundation, Ministry of Education of Brazil, Brasília, Federal District, Brazil
| | - Peter A Horn
- Institute for Transfusion Medicine, University Hospital Essen , Essen , Germany
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42
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Dumontet E, Danger R, Vagefi PA, Londoño MC, Pallier A, Lozano JJ, Giral M, Degauque N, Soulillou JP, Martínez-Llordella M, Lee H, Latournerie M, Boudjema K, Dulong J, Tarte K, Sanchez-Fueyo A, Feng S, Brouard S, Conchon S. Peripheral phenotype and gene expression profiles of combined liver-kidney transplant patients. Liver Int 2016; 36:401-9. [PMID: 26193627 PMCID: PMC5395096 DOI: 10.1111/liv.12917] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 07/04/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS The beneficial effect of one graft on another has been reported in combined transplantation but the associated mechanisms and biological influence of each graft have not yet been established. METHODS In multiple analyses, we explored the PBMC phenotype and signature of 45 immune-related messenger RNAs and 754 microRNAs from a total of 235 patients, including combined liver-kidney transplant recipients (CLK), patients with a liver (L-STA) or kidney (K-STA) graft only under classical immunosuppression and patients with tolerated liver (L-TOL) or kidney grafts (K-TOL). RESULTS CLK show an intermediary phenotype with a higher percentage of peripheral CD19(+) CD24(+) CD38(Low) memory B cells and Helios(+) Treg cells, two features associated with tolerance profiles, compared to L-STA and K-STA (P < 0.05, P < 0.01). Very few miRNA were significantly differentially expressed in CLK vs. K-STA and even fewer when compared to L-STA (35 and 8, P < 0.05). Finally, CLK are predicted to share common miRNA targets with K-TOL and even more with L-TOL (344 and 411, P = 0.005). Altogether CLK display an intermediary phenotype and gene profile, which is closer to that of liver transplant patients, with possible similarities with the profiles of tolerant patients. CONCLUSION These data suggest that CLK patients show the immunological influence of both allografts with liver having a greater influence.
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Affiliation(s)
- Erwan Dumontet
- INSERM UMR 1064, Nantes, France,CHU de Nantes, ITUN, Nantes, France,Université de Nantes, Nantes, France,Centre Hospitalier Universitaire Pontchaillou, Rennes,
France
| | - Richard Danger
- INSERM UMR 1064, Nantes, France,CHU de Nantes, ITUN, Nantes, France,Department of Liver Studies, Medical Research Council (MRC)
Centre for Transplantation, School of Life Sciences & Medicine,
King’s College London University, London, UK
| | - Parsia A. Vagefi
- Division of Transplantation Surgery, Massachusetts General
Hospital, and Harvard medical school, Boston, MA, USA
| | | | - Annaïck Pallier
- INSERM UMR 1064, Nantes, France,CHU de Nantes, ITUN, Nantes, France
| | - Juan José Lozano
- Liver Unit and Bioinformatic platform, Hospital Clinic
Barcelona, Barcelona, Spain
| | - Magali Giral
- INSERM UMR 1064, Nantes, France,CHU de Nantes, ITUN, Nantes, France,Université de Nantes, Nantes, France,CIC Biothérapie, Nantes, France
| | - Nicolas Degauque
- INSERM UMR 1064, Nantes, France,CHU de Nantes, ITUN, Nantes, France
| | - Jean-Paul Soulillou
- INSERM UMR 1064, Nantes, France,CHU de Nantes, ITUN, Nantes, France,Université de Nantes, Nantes, France
| | - Marc Martínez-Llordella
- Department of Liver Studies, Medical Research Council (MRC)
Centre for Transplantation, School of Life Sciences & Medicine,
King’s College London University, London, UK,Liver Unit and Bioinformatic platform, Hospital Clinic
Barcelona, Barcelona, Spain
| | - Herman Lee
- Department of Surgery, Division of Transplantation,
University of California, San Francisco, CA, USA
| | | | - Karim Boudjema
- Centre Hospitalier Universitaire Pontchaillou, Rennes,
France
| | - Joelle Dulong
- Centre Hospitalier Universitaire Pontchaillou, Rennes,
France,EFS Bretagne, Rennes, France,INSERM UMR 917, Rennes, France
| | - Karin Tarte
- Centre Hospitalier Universitaire Pontchaillou, Rennes,
France,EFS Bretagne, Rennes, France,INSERM UMR 917, Rennes, France
| | - Alberto Sanchez-Fueyo
- Department of Liver Studies, Medical Research Council (MRC)
Centre for Transplantation, School of Life Sciences & Medicine,
King’s College London University, London, UK,Liver Unit and Bioinformatic platform, Hospital Clinic
Barcelona, Barcelona, Spain
| | - Sandy Feng
- Department of Surgery, Division of Transplantation,
University of California, San Francisco, CA, USA
| | - Sophie Brouard
- INSERM UMR 1064, Nantes, France,CHU de Nantes, ITUN, Nantes, France,Université de Nantes, Nantes, France,CIC Biothérapie, Nantes, France,CHU Nantes, CRB, Nantes, France
| | - Sophie Conchon
- INSERM UMR 1064, Nantes, France,Université de Nantes, Nantes, France
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43
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Prominent HLA-G Expression in Liver Disease But Not After Liver Transplantation. Transplantation 2015; 99:2514-22. [DOI: 10.1097/tp.0000000000000761] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Djurisic S, Skibsted L, Hviid TVF. A Phenotypic Analysis of Regulatory T Cells and Uterine NK Cells from First Trimester Pregnancies and Associations with HLA-G. Am J Reprod Immunol 2015; 74:427-44. [DOI: 10.1111/aji.12421] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 07/20/2015] [Indexed: 01/08/2023] Open
Affiliation(s)
- Snezana Djurisic
- Department of Clinical Biochemistry; Centre for Immune Regulation and Reproductive Immunology (CIRRI); Copenhagen University Hospital (Roskilde); University of Copenhagen; Roskilde Denmark
| | - Lillian Skibsted
- Department of Obstetrics and Gynaecology; Copenhagen University Hospital (Roskilde); Roskilde Denmark
| | - Thomas Vauvert F. Hviid
- Department of Clinical Biochemistry; Centre for Immune Regulation and Reproductive Immunology (CIRRI); Copenhagen University Hospital (Roskilde); University of Copenhagen; Roskilde Denmark
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45
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Amiot L, Vu N, Samson M. Biology of the immunomodulatory molecule HLA-G in human liver diseases. J Hepatol 2015; 62:1430-7. [PMID: 25772038 DOI: 10.1016/j.jhep.2015.03.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Revised: 02/05/2015] [Accepted: 03/02/2015] [Indexed: 01/16/2023]
Abstract
The non-classical human leukocyte antigen-G (HLA-G), plays an important role in inducing tolerance, through its immunosuppressive effects on all types of immune cells. Immune tolerance is a key issue in the liver, both in liver homeostasis and in the response to liver injury or cancer. It would therefore appear likely that HLA-G plays an important role in liver diseases. Indeed, this molecule was recently shown to be produced by mast cells in the livers of patients infected with hepatitis C virus (HCV). Furthermore, the number of HLA-G-positive mast cells was significantly associated with fibrosis progression. The generation of immune tolerance is a role common to both HLA-G, as a molecule, and the liver, as an organ. This review provides a summary of the evidence implicating HLA-G in liver diseases. In the normal liver, HLA-G transcripts can be detected, but there is no HLA-G protein. However, HLA-G protein is detectable in the liver tissues and/or plasma of patients suffering from hepatocellular carcinoma, hepatitis B or C, or visceral leishmaniasis and in liver transplant recipients. The cells responsible for producing HLA-G differ between diseases. HLA-G expression is probably induced by microenvironmental factors, such as cytokines. The expression of HLA-G receptors, such as ILT2, ILT4, and KIRD2L4, on liver cells has yet to be investigated, but these receptors have been detected on all types of immune cells, and such cells are present in liver. The tolerogenic properties of HLA-G explain its deleterious effects in cancers and its beneficial effects in transplantation. Given the key role of HLA-G in immune tolerance, new therapeutic agents targeting HLA-G could be tested for the treatment of these diseases in the future.
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Affiliation(s)
- Laurence Amiot
- Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement & Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Fédération de Recherche BioSit de Rennes UMS 3480, F-35043 Rennes, France; Department of Biology, University Hospital Pontchaillou, CHU Pontchaillou, Rennes, France.
| | - Nicolas Vu
- Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement & Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Fédération de Recherche BioSit de Rennes UMS 3480, F-35043 Rennes, France
| | - Michel Samson
- Institut National de la Santé et de la Recherche Médicale (Inserm), U.1085, Institut de Recherche Santé Environnement & Travail (IRSET), F-35043 Rennes, France; Université de Rennes 1, F-35043 Rennes, France; Fédération de Recherche BioSit de Rennes UMS 3480, F-35043 Rennes, France
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46
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EXP CLIN TRANSPLANTExp Clin Transplant 2015; 13. [DOI: 10.6002/ect.mesot2014.p225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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47
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Poláková K, Bandžuchová H, Žilinská Z, Chreňová S, Kuba D, Russ G. Analysis of HLA-G expression in serum and biopsy samples of kidney transplant recipients. Immunobiology 2015; 220:533-7. [DOI: 10.1016/j.imbio.2014.10.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 10/17/2014] [Accepted: 10/20/2014] [Indexed: 01/05/2023]
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48
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LeMaoult J, Caumartin J, Daouya M, Switala M, Rebmann V, Arnulf B, Carosella ED. Trogocytic intercellular membrane exchanges among hematological tumors. J Hematol Oncol 2015; 8:24. [PMID: 25887663 PMCID: PMC4371622 DOI: 10.1186/s13045-015-0114-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 01/17/2015] [Indexed: 01/01/2023] Open
Abstract
Trogocytosis is the transfer of plasma membrane fragments and the molecules they contain between one donor and one acceptor/acquirer cell. Through trogocytosis, acceptor cells temporarily display and use cell-surface molecules they do not express themselves, but borrow from other cells. Here, we investigated whether liquid tumors possessed a trogocytic capability, if immune escape molecules could be acquired by tumor cells, transferred between cells of the same tumor, and if this could benefit the tumor as a whole.For this, we investigated trogocytosis in hematological cell lines and freshly isolated hematological tumor cells. We demonstrate that hematological tumor lines possess a trogocytic capability that allows them to capture membranes that contain the immune-inhibitory molecule HLA-G from allogeneic as well as from autologous sources. We further show that freshly isolated hematological tumor cells also possess these capabilities. This work reports for the first time the trogocytic capabilities of liquid tumor cells and introduces the notion of immune escape strategy sharing among tumor cells through trogocytosis of membrane-bound immune-inhibitory molecules.
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Affiliation(s)
- Joel LeMaoult
- CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France. .,University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d'Hematologie, Saint-Louis Hospital, Paris, France.
| | - Julien Caumartin
- CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France. .,University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d'Hematologie, Saint-Louis Hospital, Paris, France. .,Biology and Biotechnology Ph.D. Program, Univ Paris Diderot, Sorbonne Paris Cite, Paris, France.
| | - Marina Daouya
- CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France. .,University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d'Hematologie, Saint-Louis Hospital, Paris, France.
| | - Magdalena Switala
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany.
| | - Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany.
| | - Bertrand Arnulf
- Département d'Immuno-Hématologie, Hôpital Saint-Louis, Paris, France.
| | - Edgardo D Carosella
- CEA, Institute of Emerging Diseases and Innovative Therapies (iMETI), Research Division in Hematology and Immunology (SRHI), Saint-Louis Hospital, Paris, France. .,University Paris Diderot, Sorbonne Paris Cité, UMR E_5 Institut Universitaire d'Hematologie, Saint-Louis Hospital, Paris, France.
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49
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Amodio G, Comi M, Tomasoni D, Gianolini ME, Rizzo R, LeMaoult J, Roncarolo MG, Gregori S. HLA-G expression levels influence the tolerogenic activity of human DC-10. Haematologica 2015; 100:548-57. [PMID: 25661445 DOI: 10.3324/haematol.2014.113803] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule with known immune-modulatory functions. Our group identified a subset of human dendritic cells, named DC-10, that induce adaptive interleukin-10-producing T regulatory type 1 (Tr1) cells via the interleukin-10-dependent HLA-G/ILT4 pathway. In this study we aimed at defining the role of HLA-G in DC-10-mediated Tr1 cell differentiation. We analyzed phenotype, functions, and genetic variations in the 3' untranslated region of the HLA-G locus of in vitro-differentiated DC-10 from 67 healthy donors. We showed that HLA-G expression on DC-10 is donor-dependent. Functional studies demonstrated that DC-10, independently of HLA-G expression, secrete interleukin-10 and negligible levels of interleukin-12. Interestingly, DC-10 with high HLA-G promote allo-specific anergic T cells that contain a significantly higher frequency of Tr1 cells, defined as interleukin-10-producing (P=0.0121) or CD49b(+)LAG-3(+) (P=0.0031) T cells, compared to DC-10 with low HLA-G. We found that the HLA-G expression on DC-10 is genetically imprinted, being associated with specific variations in the 3' untranslated region of the gene, and it may be finely tuned by microRNA-mediated post-transcriptional regulation. These data highlight the important role of HLA-G in boosting DC-10 tolerogenic activity and confirm that interleukin-10 production by DC-10 is necessary but not sufficient to promote Tr1 cells at high frequency. These new insights into the role of HLA-G in DC-10-mediated induction of Tr1 cells provide additional information for clinical use in Tr1- or DC-10-based cell therapy approaches.
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Affiliation(s)
- Giada Amodio
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy
| | - Michela Comi
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy Ph.D Program in Translational and Molecular Medicine (DIMET), University of Milan-Bicocca, Italy
| | - Daniela Tomasoni
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Monica Emma Gianolini
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy Department of Public Health and Cell Biology, Tor Vergata University, Rome, Italy
| | - Roberta Rizzo
- Department of Medical Sciences, Section of Microbiology, University of Ferrara, Italy
| | - Joël LeMaoult
- Service de Recherches en Hémato-Immunologie, CEA-DSV-DRM, Hôpital Saint-Louis, IUH, Paris, France
| | - Maria-Grazia Roncarolo
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy
| | - Silvia Gregori
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
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50
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Brugière O, Thabut G, Krawice-Radanne I, Rizzo R, Dauriat G, Danel C, Suberbielle C, Mal H, Stern M, Schilte C, Pretolani M, Carosella ED, Rouas-Freiss N. Role of HLA-G as a predictive marker of low risk of chronic rejection in lung transplant recipients: a clinical prospective study. Am J Transplant 2015; 15:461-71. [PMID: 25488753 DOI: 10.1111/ajt.12977] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 08/04/2014] [Accepted: 08/07/2014] [Indexed: 01/25/2023]
Abstract
Human leukocyte antigen G (HLA-G) expression is thought to be associated with a tolerance state following solid organ transplantation. In a lung transplant (LTx) recipient cohort, we assessed (1) the role of HLA-G expression as a predictor of graft acceptance, and (2) the relationship between (i) graft and peripheral HLA-G expression, (ii) HLA-G expression and humoral immunity and (iii) HLA-G expression and lung microenvironment. We prospectively enrolled 63 LTx recipients (median follow-up 3.26 years [min: 0.44-max: 5.03]). At 3 and 12 months post-LTx, we analyzed graft HLA-G expression by immunohistochemistry, plasma soluble HLA-G (sHLA-G) level by enzyme-linked immunosorbent assay, bronchoalveolar lavage fluid (BALF) levels of cytokines involved in chronic lung allograft dysfunction (CLAD) and anti-HLA antibodies (Abs) in serum. In a time-dependent Cox model, lung HLA-G expression had a protective effect on CLAD occurrence (hazard ratio: 0.13 [0.03-0.58]; p = 0.008). The same results were found when computing 3-month and 1-year conditional freedom from CLAD (p = 0.03 and 0.04, respectively [log-rank test]). Presence of anti-HLA Abs was inversely associated with graft HLA-G expression (p = 0.02). Increased BALF level of transforming growth factor-β was associated with high plasma sHLA-G level (p = 0.02). In conclusion, early graft HLA-G expression in LTx recipients with a stable condition was associated with graft acceptance in the long term.
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Affiliation(s)
- O Brugière
- Service de Pneumologie B et de Transplantation Pulmonaire, Centre Hospitalier Universitaire (CHU) Bichat-Claude Bernard, Paris, France; Faculté de Médecine Denis Diderot, Université Paris 7, Paris, France; Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; DHU Fire, Paris, France; CEA, Institut des Maladies Emergentes et des Therapies Innovantes (IMETI), Service de Recherche en Hemato-Immunologie (SRHI), Hopital Saint-Louis, Paris, France; Sorbonne Paris Cité, University Paris Diderot, IUH, Hopital Saint-Louis, Paris, France
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