Follicular regulatory T cells inhibit the development of granzyme B-expressing follicular helper T cells.
Follicular regulatory T cells inhibit the development of granzyme B-expressing follicular helper T cells.
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DOI：
10.1172/jci.insight.128076
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发表时间：
2019-08
期刊：
影响因子：
8
通讯作者：
Markus M. Xie;Shuyi Fang;Qiang Chen;Hong Liu;Jun Wan;A. Dent
中科院分区：
文献类型：
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作者：
Markus M. Xie;Shuyi Fang;Qiang Chen;Hong Liu;Jun Wan;A. Dent
在生发中心(GC)反应中发现T滤泡调节(TFR)细胞，并帮助形成抗体(Ab)反应。然而，TFR细胞在GC中的确切作用是有争议的。在这里，我们使用TFR细胞发育受损的小鼠(Bcl6-Flox/Foxp3-cre，或Bcl6FC小鼠)、TFR细胞发育增强的小鼠(Blimp1-Flox/Foxp3-cre，或Blimp1FC小鼠)和两种不同的免疫方法来研究TFR细胞的功能。出乎意料的是，GC B细胞水平与TFR细胞水平呈正相关。利用基因图谱的方法，我们发现来自TFR缺陷小鼠的TFH细胞表现出颗粒酶B(GZMB)和其他效应CD8+T细胞基因的强烈上调，其中许多基因是STAT4依赖的。TfR基因缺陷小鼠的TFH细胞中细胞毒基因表达上调最高，而Foxp3+调节性T细胞(Bcl6-Flox/Prdm1-Flox/Foxp3-cre[DKO]小鼠)中Blimp1也缺失。颗粒酶B和Eomesodermin表达的TFH细胞与较高的GC B细胞凋亡率相关。DKO小鼠Klrg1+TFH细胞表达较高水平的Gzmb。我们的数据显示，TFR细胞抑制异常的细胞毒性TFH细胞的发展，并且细胞毒性TFH细胞的存在与较低的GC和抗体应答相关。我们的数据表明，我们认为TFR细胞帮助GC反应的一种新的作用机制。
T follicular regulatory (TFR) cells are found in the germinal center (GC) response and help shape the antibody (Ab) response. However, the precise role of TFR cells in the GC is controversial. Here, we addressed TFR cell function using mice with impaired TFR cell development (Bcl6-flox/Foxp3-cre, or Bcl6FC mice), mice with augmented TFR cell development (Blimp1-flox/Foxp3-cre, or Blimp1FC mice), and two different methods of immunization. Unexpectedly, GC B cell levels positively correlated with TFR cell levels. Using a gene profiling approach, we found that TFH cells from TFR-deficient mice showed strong upregulation of granzyme B (Gzmb) and other effector CD8+ T cell genes, many of which were Stat4 dependent. The upregulation of cytotoxic genes was the highest in TFH cells from TFR-deficient mice where Blimp1 was also deleted in Foxp3+ regulatory T cells (Bcl6-flox/Prdm1-flox/Foxp3-cre [DKO] mice). Granzyme B- and Eomesodermin-expressing TFH cells correlated with a higher rate of apoptotic GC B cells. Klrg1+ TFH cells from DKO mice expressed higher levels of Gzmb. Our data show that TFR cells repress the development of abnormal cytotoxic TFH cells, and the presence of cytotoxic TFH cells correlates with a lower GC and Ab response. Our data show what we believe is a novel mechanism of action for TFR cells helping the GC response.