Immune cell-derived C3a and C5a costimulate human T cell alloimmunity.
Immune cell-derived C3a and C5a costimulate human T cell alloimmunity.
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DOI：
10.1111/ajt.12405
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Heeger PS
中科院分区：
文献类型：
--
作者：
Cravedi P;Leventhal J;Lakhani P;Ward SC;Donovan MJ;Heeger PS
新出现的证据表明，补体为鼠T细胞提供共刺激信号，但补体是否影响人T细胞仍不清楚。我们观察到补体激活产物C3 a和C5 a的生产过程中，在体外培养的人T细胞响应同种异体树突状细胞（DC）。这两个伙伴表达C3 a（C3 aR）和C5 a（C5 aR）的受体，C3 aR和C5 aR拮抗剂抑制T细胞增殖。重组C3 a/C5 a促进CD 4 + T细胞扩增，绕过CTLA 4-IG的抑制作用，并诱导AKT磷酸化，后者将C3 aR/C5 aR与已知的T细胞信号传导途径生物化学连接。通过siRNA敲低DC C3降低DC C3 a/C5 a产生减少了T细胞同种异体应答。相反，下调补体调节蛋白衰变加速因子的DC表达增加了免疫细胞C3 a/C5 a并增强了T细胞增殖，将抗原呈递细胞鉴定为主要的补体来源。药理学C5 aR阻断剂降低了人PBMC的NOD scid γcnull小鼠受体的移植物抗宿主病（GVHD）评分，延长了生存期，并抑制了T细胞应答，验证了该机制适用于体内。我们的研究结果明确证明免疫细胞衍生的补体影响人类T细胞免疫，并为未来靶向C3 aR/C5 aR作为人类GVHD和器官移植排斥治疗的研究提供基础。
Emerging evidence indicates that complement provides costimulatory signals for murine T cells but whether complement impacts human T cells remains unclear. We observed production of complement activation products C3a and C5a during in vitro cultures of human T cells responding to allogeneic dendritic cells (DC). Both partners expressed the receptors for C3a (C3aR) and C5a (C5aR), and C3aR- and C5aR-antagonists inhibited T cell proliferation. Recombinant C3a/C5a promoted CD4+ T cell expansion, bypassed the inhibitory effects of CTLA4-Ig, and induced AKT phosphorylation, the latter biochemically linking C3aR/C5aR to known T cell signaling pathways. Lowering DC C3a/C5a production by siRNA knockdown of DC C3 reduced T cell alloresponses. Conversely downregulating DC expression of the complement regulatory protein decay accelerating factor increased immune cell C3a/C5a and augmented T cell proliferation, identifying antigen presenting cells as the dominant complement source. Pharmacological C5aR blockade reduced graft versus host disease (GVHD) scores, prolonged survival, and inhibited T cell responses in NOD scid γcnull mouse recipients of human PBMCs, verifying that the mechanisms apply in vivo. Together our findings unequivocally document that immune cell-derived complement impacts human T cell immunity and provide the foundation for future studies targeting C3aR/C5aR as treatments of GVHD and organ transplant rejection in humans.
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