Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells
Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells
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DOI：
10.1016/j.immuni.2008.02.001
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发表时间：
2008-03-01
期刊：
影响因子：
32.4
通讯作者：
Medof, M. Edward
中科院分区：
文献类型：
--
作者：
Strainic, Michael G.;Liu, Jinbo;Medof, M. Edward
共刺激信号对T细胞活化至关重要，但其作用如何介导仍不完全表征。在这里，我们展示了当地生产的C5 a和C3 a。过敏毒素与APC和T细胞上的G蛋白偶联受体（GPCR）C5 aR和C3 aR相互作用，在CD 28和CD 40 L信号传导的上游和下游，整体参与T细胞增殖和分化。禁用这些相互作用减少MHC 11类和共刺激分子的表达，并显着减少T细胞的反应。重要的是，通过添加C5 a重建由Cd 80（-/-）Cd 86（-/-）和Cd 40（-/-）APC引起的受损的T细胞活化。或C3 a。C5 aR和C3 aR通过PI-3激酶-γ依赖性AKT磷酸化介导其作用，提供GPCR信号传导、CD 28共刺激和T细胞存活之间的联系。因此，这些局部旁分泌和自分泌相互作用在幼稚T细胞中组成性地运作以维持活力，并且它们通过同源APC伴侣的扩增因此对T细胞共刺激至关重要。
Costimulatory signals are critical to T cell activation, but how their effects are mediated remains incompletely characterized. Here, we demonstrate that locally produced C5a and C3a. anaphylatoxins interacting with their G protein-coupled receptors (GPCRs), C5aR and C3aR, on APCs and T cells both upstream and downstream of CD28 and CD40L signaling are integrally involved in T cell proliferation and differentiation. Disabling these interactions reduced MHC class 11 and costimulatory-molecule expression and dramatically diminished T cell responses. Importantly, impaired T cell activation by Cd80(-/-)Cd86(-/-) and Cd40(-/-) APCs was reconstituted by added C5a. or C3a. C5aR and C3aR mediated their effects via PI-3 kinase-gamma-dependent AKT phosphorylation, providing a link between GPCR signaling, CD28 costimulation, and T cell survival. These local paracrine and autocrine interactions thus operate constitutively in naive T cells to maintain viability, and their amplification by cognate APC partners thus is critical to T cell costimulation.