Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis
Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis
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DOI：
10.1182/blood-2008-04-151068
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发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
Heeger, Peter S.
中科院分区：
文献类型：
--
作者：
Lalli, Peter N.;Strainic, Michael G.;Heeger, Peter S.
我们最近的研究表明，免疫细胞产生的补体为初始CD4(+) T细胞提供共刺激和生存信号。在效应细胞扩增过程中是否同样需要这些信号，以及将局部产生的补体与t细胞存活联系起来的分子途径尚不清楚。为了解决这个问题，我们在体外和体内用缺乏补体调节蛋白、衰变加速因子（DAF）和/或补体成分C3的抗原呈递细胞（APCs）刺激单克隆和多克隆T细胞。我们发现daf缺陷APCs诱导的t细胞扩增随着t细胞凋亡的减少而增强，而C3(-/-) APCs诱导的t细胞扩增由于t细胞凋亡的增强而减弱。这些作用可以追溯到局部产生的C5a，它通过与T细胞表达的C5aR结合，增强Bcl-2的表达并阻止Fas的上调。结果表明，T细胞中的C5aR信号转导对于实现最佳T细胞扩增以及维持初始细胞活力非常重要，并且通过抑制程序性细胞死亡来实现。
Our recent studies have shown that immune cell-produced complement provides costimulatory and survival signals to naive CD4(+) T cells. Whether these signals are similarly required during effector cell expansion and what molecular pathways link locally produced complement to T-cell survival were not clarified. To address this, we stimulated monoclonal and polyclonal T cells in vitro and in vivo with antigen-presenting cells (APCs) deficient in the complement regulatory protein, decay accelerating factor (DAF), and/or the complement component C3. We found that T-cell expansion induced by DAF-deficient APCs was augmented with diminished T-cell apoptosis, whereas T-cell expansion induced by C3(-/-) APCs was reduced because of enhanced T-cell apoptosis. These effects were traced to locally produced C5a, which through binding to T cell-expressed C5aR, enhanced expression of Bcl-2 and prevented Fas up-regulation. The results show that C5aR signal transduction in T cells is important to allow optimal T-cell expansion, as well as to maintain naive cell viability, and does so by suppressing programmed cell death.