Absence of recipient C3aR1 signaling limits expansion and differentiation of alloreactive CD8+ T cell immunity and prolongs murine cardiac allograft survival
Absence of recipient C3aR1 signaling limits expansion and differentiation of alloreactive CD8+ T cell immunity and prolongs murine cardiac allograft survival
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DOI：
10.1111/ajt.15222
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发表时间：
2019-06-01
影响因子：
8.8
通讯作者：
Heeger, Peter S.
中科院分区：
文献类型：
--
作者：
Mathern, Douglas R.;Horwitz, Julian K.;Heeger, Peter S.
同种异体反应性 CD8(+) T 细胞是介导小鼠心脏同种异体移植排斥反应的主要效应细胞，其激活、分化和扩增需要同种异体识别、共刺激和细胞因子引发的信号。虽然之前的研究表明同种异体反应性 CD4(+) T 细胞免疫需要免疫细胞产生和局部激活的补体，但 C3a 受体 1 (C3aR1) 信号是否以及如何影响移植结果以及将 C3aR1 与同种异体反应性 CD8(+) T 细胞激活/扩增联系起来的机制仍不清楚。在此，我们表明，与他克莫司治疗的对照组相比，受体 C3aR1 缺陷或药理学 C3aR1 阻断与他克莫司协同作用，可显着延长同种异体移植物的生存期（中位生存时间 21 天与 14 天，P < .05）。受体C3aR1缺陷使移植后供体反应性CD8(+) T细胞的频率降低两倍。将初始WT或C3ar1(-/-) CD8(+) T细胞过继转移至同基因WT或C3ar1(-/-)同种异体移植受体中表明，T细胞表达的C3aR1诱导CD8(+) T增殖、mTOR激活和转录因子T-bet表达。宿主C3aR1通过放大抗原呈递细胞共刺激分子的表达和先天细胞因子的产生来间接促进同种异体反应性CD8+T细胞增殖/扩增。除了扩大机制洞察之外，我们的研究结果还确定 C3aR1 是未来旨在改善人类移植结果的研究的可测试治疗靶点。
Activation, differentiation, and expansion of alloreactive CD8(+) T cells, the dominant effectors that mediate murine heart allograft rejection, requires allorecognition, costimulation, and cytokine-initiated signals. While previous work showed that alloreactive CD4(+) T cell immunity entails immune cell-produced and locally activated complement, whether and how C3a receptor 1 (C3aR1) signaling impacts transplant outcomes and the mechanisms linking C3aR1 to alloreactive CD8(+) T cell activation/expansion remain unclear. Herein we show that recipient C3aR1 deficiency or pharmacological C3aR1 blockade synergizes with tacrolimus to significantly prolong allograft survival versus tacrolimus-treated controls (median survival time 21 vs. 14 days, P < .05). Recipient C3aR1-deficiency reduced the frequencies of posttransplant, donor-reactive CD8(+) T cells twofold. Reciprocal adoptive transfers of naive WT or C3ar1(-/-) CD8(+) T cells into syngeneic WT or C3ar1(-/-) allograft recipients showed that T cell-expressed C3aR1 induces CD8(+) T proliferation, mTOR activation and transcription factor T-bet expression. Host C3aR1 indirectly facilitates alloreactive CD8(+) T cell proliferation/expansion by amplifying antigen presenting cell costimulatory molecule expression and innate cytokine production. In addition to expanding mechanistic insight, our findings identify C3aR1 as a testable therapeutic target for future studies aimed at improving human transplant outcomes.