Extracellular matrix protein 1 promotes follicular helper T cell differentiation and antibody production
Extracellular matrix protein 1 promotes follicular helper T cell differentiation and antibody production
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细胞外基质蛋白 1 促进滤泡辅助 T 细胞分化和抗体产生
DOI：
10.1073/pnas.1801196115
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发表时间：
2018-08-21
影响因子：
11.1
通讯作者：
Sun, Bing
中科院分区：
文献类型：
--
作者：
He, Lan;Gu, Wangpeng;Sun, Bing
TFH细胞分化和抗原特异性抗体的产生对体液反应至关重要。在这项工作中，我们发现细胞外基质蛋白1 （ECM1）通过抑制IL-2-STAT5-Bcl6信号通路是t -滤泡辅助细胞（TFH）分化的关键正调节因子。重要的是，在抗原免疫和流感感染条件下，ECM1有效地增强了TFH分化、生发中心反应和中和抗体的产生，这表明ECM1可能是体内体液反应的积极调节因子。T-滤泡辅助细胞（TFH）是CD4+辅助T细胞的一个亚群，在生发中心反应中帮助生发中心（GC） b细胞分化和高亲和力抗体的产生。重要的细胞外分子是否控制TFH分化尚不完全清楚。在这里，我们证明了分泌蛋白细胞外基质蛋白1 （ECM1）对TFH分化和抗体反应至关重要。在抗原免疫小鼠模型中，缺乏ECM1抑制TFH细胞的发育，损害GC b细胞反应和抗原特异性抗体的产生。IL-6和IL-21在TFH细胞中诱导ECM1，通过下调STAT5磷酸化水平和上调Bcl6表达促进TFH分化。此外，将重组ECM1蛋白注射到感染PR8流感病毒的小鼠体内，通过增强TFH分化和中和抗体的产生，有效地促进了保护性免疫反应。总的来说，我们的数据确定ECM1是促进TFH细胞分化和抗体产生的可溶性蛋白。
Significance TFH cell differentiation and antigen-specific antibody production is critical for humoral responses. In this work, we show that extracellular matrix protein 1 (ECM1) is a critical positive regulator in T-follicular helper (TFH) differentiation by repressing IL-2–STAT5–Bcl6 signaling pathway. Importantly, ECM1 effectively enhanced TFH differentiation, germinal center responses, and neutralizing antibody production both in antigen-immunized conditions and influenza infection, which indicate ECM1 may serve as a positive regulator for humoral responses in vivo. T-follicular helper (TFH) cells are a subset of CD4+ helper T cells that help germinal center (GC) B-cell differentiation and high-affinity antibody production during germinal center reactions. Whether important extracellular molecules control TFH differentiation is not fully understood. Here, we demonstrate that a secreted protein extracellular matrix protein 1 (ECM1) is critical for TFH differentiation and antibody response. A lack of ECM1 inhibited TFH cell development and impaired GC B-cell reactions and antigen-specific antibody production in an antigen-immunized mouse model. ECM1 was induced by IL-6 and IL-21 in TFH cells, promoting TFH differentiation by down-regulating the level of STAT5 phosphorylation and up-regulating Bcl6 expression. Furthermore, injection of recombinant ECM1 protein into mice infected with PR8 influenza virus promoted protective immune responses effectively, by enhancing TFH differentiation and neutralizing antibody production. Collectively, our data identify ECM1 as a soluble protein to promote TFH cell differentiation and antibody production.