ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells.
ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells.
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DOI：
10.26508/lsa.202201615
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发表时间：
2023-04
影响因子：
4.4
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中科院分区：
文献类型：
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ICOS信号在生发中心反应期间促进T滤泡调节细胞分化，保护自身抗体的产生。ICOS是一种T细胞共刺激受体，对Tfh细胞的生成和功能至关重要。然而，ICOS在Tfr细胞分化中的作用仍不清楚。使用Foxp 3-Cre介导的ICOS敲除（ICOS FC）小鼠，我们表明Treg谱系细胞中的ICOS缺陷大大减少了GC反应期间Tfr细胞的数量，但对常规Treg细胞的影响最小。在GC反应的早期阶段Foxp 3+细胞的单细胞转录组分析表明，ICOS通常抑制Klf 2表达以促进卵泡特征，包括Bcl 6上调。此外，ICOS共刺激促进NFAT 2的核定位，NFAT 2是CXCR 5表达的已知驱动因子。值得注意的是，ICOS FC小鼠的总体GC B细胞输出量不变，但显示出自身反应性B细胞扩增的迹象，同时沿着自身抗体滴度升高。因此，我们的研究表明，ICOS共刺激是至关重要的Tfr细胞分化，并强调了Tfr细胞在GC反应过程中维持体液免疫耐受的重要性。
ICOS signaling promotes T follicular regulatory cell differentiation during germinal center reaction safeguarding against autoantibody production. ICOS is a T-cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre–mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 up-regulation. Furthermore, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B-cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.