Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo
Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo
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DOI：
10.1016/j.jaut.2014.09.002
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发表时间：
2015-01-01
影响因子：
12.8
通讯作者：
Caligiuri, Giuseppina
中科院分区：
文献类型：
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作者：
Clement, Marc;Fornasa, Giulia;Caligiuri, Giuseppina
CD31是一种表达在T和B淋巴细胞上的反式亲和性抑制受体，它驱动相互作用的白细胞相互分离。有趣的是，T细胞CD31分子重新定位到免疫突触(IS)，在那里T和B细胞建立了稳定的相互作用。在这里，我们证明了能够驱动抑制信号的完整CD31分子集中在IS的外围，但被排除在IS的中心。在这个部位，当细胞建立最密切的接触时，CD31分子被切割，蛋白质的大部分胞外部分，包括反式亲性结合部位，从细胞表面脱落。缺乏CD31反式亲性结合部位的T细胞很容易与B细胞建立稳定的相互作用；相反，CD31信号激动剂抑制T/B IS的形成以及随之而来的辅助T细胞的激活和功能。共聚焦显微镜和流式细胞仪对实验性T/B细胞的分析表明，CD31激动剂的T细胞抑制作用依赖于SHP-2信号，从而降低ZAP70的磷酸化。类风湿关节炎患者的滑膜组织活检分析表明，T细胞CD31分子被排除在体内T/B细胞突触的中心。有趣的是，体内应用CD31激动剂显著减轻了DBA1/J小鼠胶原性关节炎的临床症状的发展。综上所述，我们的数据表明，T细胞共抑制受体CD31阻止功能性T/B免疫突触的形成，旨在维持CD31信号的治疗策略将减弱体内自身免疫反应的发展。(C)2014爱思唯尔有限公司。保留所有权利。
CD31, a trans-homophilic inhibitory receptor expressed on both T- and B-lymphocytes, drives the mutual detachment of interacting leukocytes. Intriguingly, T cell CD31 molecules relocate to the immunological synapse (IS), where the T and B cells establish a stable interaction.Here, we show that intact CD31 molecules, which are able to drive an inhibitory signal, are concentrated at the periphery of the IS but are excluded from the center of the IS. At this site, were the cells establish the closest contact, the CD31 molecules are cleaved, and most of the extracellular portion of the protein, including the trans-homophilic binding sites, is shed from the cell surface.T cells lacking CD31 trans-homophilic binding sites easily establish stable interactions with B cells; at the opposite, CD31 signaling agonists inhibit T/B IS formation as well as the ensuing helper T cell activation and function. Confocal microscopy and flow cytometry analysis of experimental T/B IS shows that the T cell inhibitory effects of CD31 agonists depend on SHP-2 signaling, which reduces the phosphorylation of ZAP70.The analysis of synovial tissue biopsies from patients affected by rheumatoid arthritis showed that T cell CD31 molecules are excluded from the center of the T/B cell synapses in vivo. Interestingly, the administration of CD31 agonists in vivo significantly attenuated the development of the clinical signs of collagen-induced arthritis in DBA1/J mice.Altogether, our data indicate that the T cell co-inhibitory receptor CD31 prevents the formation of functional T/B immunological synapses and that therapeutic strategies aimed at sustaining CD31 signaling will attenuate the development of autoimmune responses in vivo. (C) 2014 Elsevier Ltd. All rights reserved.