Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling
BackgroundDecoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cell-mediated rejection (ACMR) remain unknown.Meth...
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.879648/full |
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| author | Shuo-Chun Weng Shuo-Chun Weng Shuo-Chun Weng Mei-Chin Wen Mei-Chin Wen Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Nien-Jung Chen Nien-Jung Chen Der-Cherng Tarng Der-Cherng Tarng Der-Cherng Tarng Der-Cherng Tarng |
| author_facet | Shuo-Chun Weng Shuo-Chun Weng Shuo-Chun Weng Mei-Chin Wen Mei-Chin Wen Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Nien-Jung Chen Nien-Jung Chen Der-Cherng Tarng Der-Cherng Tarng Der-Cherng Tarng Der-Cherng Tarng |
| author_sort | Shuo-Chun Weng |
| collection | DOAJ |
| description | BackgroundDecoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cell-mediated rejection (ACMR) remain unknown.MethodsWe generated DcR3 transgenic (Tg) mice and mice with high DcR3 expression (HDE) to study both in vivo and in vitro. FasR RNA knockdown in immortalized CD4+CD8+ T-cells was used to survey the role of DcR3 on FasR/Fas-associated protein with death domain (FADD)/caspase 8 pathway and its cross-link to TNF receptor-associated factor 1 (TNFR1)-associated death domain protein (TRADD) in suppressing TNFR1. TNF/TRADD knockout mice were used to show the importance of TNF adaptor protein.ResultsDcR3.Fc suppressed C57BL/6 female T-cell activation and transformation into CD4+CD69+, CD4+CD44+, and CD4+CD25+Foxp3+ when compared with isotype IgG1 and its co-treatment with FasL/TRAIL after exposing to bone marrow-derived dendritic cells (BMDCs) that carried alloantigen with male H-Y and minor antigenic determinant. Interleukin-17 and interferon-γ productions by BMDC-activated T-cells were lowered after co-treating with DcR3.Fc. DcR3.Fc induced effector T-cells (Teffs) and was susceptible to FasR-mediated apoptosis through the FADD/TRADD/caspase 8 pathway. After exposing to DcR3.Fc, TRADD was silenced, likely turning down the inflammatory response. The systemic effects of DcR3 Tg mice and HDE phenotype induced by the promoter of cytomegalovirus not only attenuated ACMR severity but also ameliorated the high serum creatinine and blood urea nitrogen levels even with high T-cell exposure frequencies. Besides this, DcR3 has minor biological effects on both MHC-matched and MHC-mismatched models.ConclusionsHigh DcR3 doses protect renal tubular epithelial cells from acute T-cell attack during the T-cell priming stage via interfering with TNF ligand-mediated reverse signaling and possibly promoting Teff apoptosis through FasR upregulation. Our findings supported that the decoy receptor is involved in T-cell modulation in kidney transplant rejection. |
| first_indexed | 2024-04-13T17:59:38Z |
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| issn | 1664-3224 |
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| last_indexed | 2024-04-13T17:59:38Z |
| publishDate | 2022-06-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-29f78f4249c34bf8b79eebe7bd043cf62022-12-22T02:36:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.879648879648Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse SignalingShuo-Chun Weng0Shuo-Chun Weng1Shuo-Chun Weng2Mei-Chin Wen3Mei-Chin Wen4Shie-Liang Hsieh5Shie-Liang Hsieh6Shie-Liang Hsieh7Shie-Liang Hsieh8Nien-Jung Chen9Nien-Jung Chen10Der-Cherng Tarng11Der-Cherng Tarng12Der-Cherng Tarng13Der-Cherng Tarng14Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, TaiwanInstitute of Clinical Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, TaiwanCenter for Geriatrics and Gerontology, Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, TaiwanSchool of Medicine, Chung Shan Medical University, Taichung, TaiwanDepartment of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, TaiwanInstitute of Clinical Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, TaiwanGenomics Research Center, Academia Sinica, Taipei, TaiwanDepartment of Medical Research and Education, Taipei Veterans General Hospital, Taipei, TaiwanDepartment of Clinical Pharmacy, Taipei Medical University, Taipei, TaiwanInstitute of Microbiology and Immunology, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan0Inflammation and Immunity Research Center, National Yang Ming Chiao Tung University, Taipei, TaiwanInstitute of Clinical Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan1Department and Institute of Physiology, National Yang Ming Chiao Tung University, Taipei, Taiwan2Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan3Center for Intelligent Drug Systems and Smart Bio-devices, National Yang Ming Chiao Tung University, Hsinchu, TaiwanBackgroundDecoy receptor 3 (DcR3) belongs to the tumor necrosis factor (TNF) receptor superfamily and neutralizes TNF ligands, including FasL and TRAIL, to prevent T activation during T-cell priming. However, the cellular mechanisms underlying acute cell-mediated rejection (ACMR) remain unknown.MethodsWe generated DcR3 transgenic (Tg) mice and mice with high DcR3 expression (HDE) to study both in vivo and in vitro. FasR RNA knockdown in immortalized CD4+CD8+ T-cells was used to survey the role of DcR3 on FasR/Fas-associated protein with death domain (FADD)/caspase 8 pathway and its cross-link to TNF receptor-associated factor 1 (TNFR1)-associated death domain protein (TRADD) in suppressing TNFR1. TNF/TRADD knockout mice were used to show the importance of TNF adaptor protein.ResultsDcR3.Fc suppressed C57BL/6 female T-cell activation and transformation into CD4+CD69+, CD4+CD44+, and CD4+CD25+Foxp3+ when compared with isotype IgG1 and its co-treatment with FasL/TRAIL after exposing to bone marrow-derived dendritic cells (BMDCs) that carried alloantigen with male H-Y and minor antigenic determinant. Interleukin-17 and interferon-γ productions by BMDC-activated T-cells were lowered after co-treating with DcR3.Fc. DcR3.Fc induced effector T-cells (Teffs) and was susceptible to FasR-mediated apoptosis through the FADD/TRADD/caspase 8 pathway. After exposing to DcR3.Fc, TRADD was silenced, likely turning down the inflammatory response. The systemic effects of DcR3 Tg mice and HDE phenotype induced by the promoter of cytomegalovirus not only attenuated ACMR severity but also ameliorated the high serum creatinine and blood urea nitrogen levels even with high T-cell exposure frequencies. Besides this, DcR3 has minor biological effects on both MHC-matched and MHC-mismatched models.ConclusionsHigh DcR3 doses protect renal tubular epithelial cells from acute T-cell attack during the T-cell priming stage via interfering with TNF ligand-mediated reverse signaling and possibly promoting Teff apoptosis through FasR upregulation. Our findings supported that the decoy receptor is involved in T-cell modulation in kidney transplant rejection.https://www.frontiersin.org/articles/10.3389/fimmu.2022.879648/fulladaptor proteindecoy receptorminor antigenic determinantknockoutphenotypetransgenic mice |
| spellingShingle | Shuo-Chun Weng Shuo-Chun Weng Shuo-Chun Weng Mei-Chin Wen Mei-Chin Wen Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Shie-Liang Hsieh Nien-Jung Chen Nien-Jung Chen Der-Cherng Tarng Der-Cherng Tarng Der-Cherng Tarng Der-Cherng Tarng Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling Frontiers in Immunology adaptor protein decoy receptor minor antigenic determinant knockout phenotype transgenic mice |
| title | Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling |
| title_full | Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling |
| title_fullStr | Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling |
| title_full_unstemmed | Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling |
| title_short | Decoy Receptor 3 Suppresses T-Cell Priming and Promotes Apoptosis of Effector T-Cells in Acute Cell-Mediated Rejection: The Role of Reverse Signaling |
| title_sort | decoy receptor 3 suppresses t cell priming and promotes apoptosis of effector t cells in acute cell mediated rejection the role of reverse signaling |
| topic | adaptor protein decoy receptor minor antigenic determinant knockout phenotype transgenic mice |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.879648/full |
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