Weng Shuo-Chun, Wen Mei-Chin, Hsieh Shie-Liang, Chen Nien-Jung, Tarng Der-Cherng
Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
Institute of Clinical Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Front Immunol. 2022 Jun 2;13:879648. doi: 10.3389/fimmu.2022.879648. eCollection 2022.
Decoy 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.
We generated DcR3 transgenic (Tg) mice and mice with high DcR3 expression (HDE) to study both and . FasR RNA knockdown in immortalized CD4CD8 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.
DcR3.Fc suppressed C57BL/6 female T-cell activation and transformation into CD4CD69, CD4CD44, and CD4CD25Foxp3 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.
High DcR3 doses protect renal tubular epithelial cells from acute T-cell attack during the T-cell priming stage 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.
诱饵受体3（DcR3）属于肿瘤坏死因子（TNF）受体超家族，可中和包括FasL和TRAIL在内的TNF配体，以防止T细胞启动过程中的T细胞活化。然而，急性细胞介导的排斥反应（ACMR）的细胞机制仍不清楚。
我们制备了DcR3转基因（Tg）小鼠和高DcR3表达（HDE）小鼠，以研究两者。使用永生化CD4CD8 T细胞中的FasR RNA敲低来研究DcR3在FasR/死亡结构域相关蛋白Fas相关蛋白（FADD）/半胱天冬酶8途径中的作用及其与TNF受体相关因子1（TNFR1）相关死亡结构域蛋白（TRADD）在抑制TNFR1中的交联。使用TNF/TRADD基因敲除小鼠来证明TNF衔接蛋白的重要性。
与同型IgG1相比，DcR3.Fc在暴露于携带雄性H-Y和次要抗原决定簇的同种异体抗原的骨髓来源树突状细胞（BMDC）后，抑制了C57BL/6雌性T细胞活化并转化为CD4CD69、CD4CD44和CD4CD25Foxp3，以及它与FasL/TRAIL的联合处理。与DcR3.Fc联合处理后，BMDC激活的T细胞产生的白细胞介素-17和干扰素-γ减少。DcR3.Fc诱导效应T细胞（Teffs），并通过FADD/TRADD/半胱天冬酶8途径易受FasR介导的凋亡影响。暴露于DcR3.Fc后，TRADD沉默，可能降低了炎症反应。由巨细胞病毒启动子诱导的DcR3 Tg小鼠和HDE表型的全身效应不仅减轻了ACMR的严重程度，而且即使在高T细胞暴露频率下也改善了高血清肌酐和血尿素氮水平。除此之外，DcR3对MHC匹配和MHC不匹配模型均有轻微的生物学效应。
高剂量的DcR3在T细胞启动阶段保护肾小管上皮细胞免受急性T细胞攻击，干扰TNF配体介导的反向信号传导，并可能通过上调FasR促进Teff凋亡。我们的研究结果支持诱饵受体参与肾移植排斥反应中的T细胞调节。
