IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2.
IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2.
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DOI：
10.1038/ncomms14647
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发表时间：
2017-03-17
影响因子：
16.6
通讯作者：
King C
中科院分区：
文献类型：
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作者：
Jandl C;Liu SM;Cañete PF;Warren J;Hughes WE;Vogelzang A;Webster K;Craig ME;Uzel G;Dent A;Stepensky P;Keller B;Warnatz K;Sprent J;King C
T滤泡调节(TFR)细胞控制生发中心反应的大小和特异性，但如何调控以确保高亲和力抗体的产生尚不清楚。在这里，我们表明，这种平衡是由白介素2和白介素21的相互影响维持的。IL-21受体(IL-21R)功能缺失患者外周血中依赖IL-2的FoxP3+调节性T细胞数量增加。在小鼠中，IL-21：IL-21R的相互作用影响T滤泡细胞的表型，减少CXCR4的表达，抑制T细胞依赖免疫后TFR细胞的扩张。IL-21对小鼠TFR细胞的负性作用是细胞固有的，并与高亲和力IL-2受体(CD25)表达减少有关。BCL-6在TFR细胞中大量表达，可抑制CD25的表达，而IL-21介导的CD25抑制作用依赖于Bcl6。这些发现确定了IL-21通过限制TFR细胞增殖来增强体液免疫的机制。IL-21是毛囊辅助T细胞功能和生发中心反应的中心。在这里，作者表明，IL-21信号通过限制依赖于Bcl-6的IL-2受体的表达，直接抑制T滤泡调节细胞。
T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation. IL-21 is central to follicular helper T cell function and germinal centre responses. Here the authors show that IL-21 signalling directly inhibits T follicular regulatory cells by limiting Bcl-6-dependent IL-2 receptor expression.