Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice.
Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice.
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DOI：
10.1002/eji.201546094
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发表时间：
2016-05
影响因子：
5.4
通讯作者：
Dent AL
中科院分区：
文献类型：
--
作者：
Wu H;Chen Y;Liu H;Xu LL;Teuscher P;Wang S;Lu S;Dent AL
滤泡辅助性T（Tfh）细胞为生殖中心B（GCB）细胞提供关键帮助以进行适当的抗体产生，并且调节性T细胞的专门亚群，滤泡调节性T（Tfr）细胞调节该过程。然而，Tfr-细胞在GC中的功能还不清楚。在此，我们将Tfr细胞定义为CD 4 + Foxp 3 + CXCR 5 hi PD-1hi CD 25低TIGIT高T细胞群。此外，我们使用了一种新的小鼠模型（“Bcl 6 FC”）来删除Foxp 3 + T细胞中的Bcl 6基因，从而特异性地耗尽Tfr细胞。免疫后，Bcl 6 FC小鼠发育正常的Tfh和GCB细胞群。然而，Bcl 6 FC小鼠产生改变的抗原特异性抗体应答，具有降低的IgG滴度和显著增加的伊加。在HIV-1 gp 120“初免-加强”疫苗模型中，Bcl 6 FC小鼠也产生了对抗原的亲合力显著降低的IgG抗体。在自身免疫性狼疮模型中，我们观察到Bcl 6 FC小鼠中抗DNA伊加滴度强烈升高。此外，来自Bcl 6 FC小鼠的Tfh细胞始终产生较高水平的干扰素-γ、IL-10和IL-21。因此，Tfr细胞的丧失导致高度异常的Tfh细胞和GCB细胞应答。总的来说，我们的研究揭示了Tfr细胞在GC反应中的独特调节作用。
Follicular helper T (Tfh) cells provide crucial help to germinal center B (GCB) cells for proper antibody production, and a specialized subset of regulatory T cells, follicular regulatory T (Tfr) cells, modulate this process. However Tfr-cell function in the GC is not well understood. Here, we define Tfr cells as a CD4+ Foxp3+ CXCR5hi PD-1hi CD25low TIGIThigh T-cell population. Furthermore, we have used a novel mouse model (“Bcl6FC”) to delete the Bcl6 gene in Foxp3+ T cells and thus specifically deplete Tfr cells. Following immunization, Bcl6FC mice develop normal Tfh- and GCB-cell populations. However, Bcl6FC mice produce altered antigen-specific antibody responses, with reduced titers of IgG and significantly increased IgA. Bcl6FC mice also developed IgG antibodies with significantly decreased avidity to antigen in an HIV-1 gp120 “prime-boost” vaccine model. In an autoimmune lupus model, we observed strongly elevated anti-DNA IgA titers in Bcl6FC mice. Additionally, Tfh cells from Bcl6FC mice consistently produce higher levels of Interferon-γ, IL-10 and IL-21. Loss of Tfr cells therefore leads to highly abnormal Tfh-cell and GCB-cell responses. Overall, our study has uncovered unique regulatory roles for Tfr cells in the GC response.