TNFR2 Signaling Enhances Suppressive Abilities of Human Circulating T Follicular Regulatory Cells
TNFR2 Signaling Enhances Suppressive Abilities of Human Circulating T Follicular Regulatory Cells
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DOI：
10.4049/jimmunol.2100323
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发表时间：
2022-03-01
影响因子：
4.4
通讯作者：
Niiro, Hiroaki
中科院分区：
文献类型：
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作者：
Kawano, Shotaro;Mitoma, Hiroki;Niiro, Hiroaki
滤泡调节性 T (Tfr) 细胞是 CD4(+) T 细胞的一个子集，表达 CXCR5 并迁移至生发中心 (GC)。它们通过与滤泡辅助 T (Tfh) 和 B 细胞通讯来调节 GC 反应。 TNF抑制剂用于治疗炎症性疾病；然而，自身抗体或抗药物抗体的产生有时会引起问题。由于 TNFR2 信号传导对于调节性 T 细胞的抑制功能很重要，因此我们研究了 TNFR2 对人类 Tfr 细胞的作用。分析用 MR2-1（一种抗 TNFR2 激动剂 Ab）刺激的 Tfr 细胞的细胞增殖、Foxp3 表达和表面分子。检查了与 MR2-1 刺激的 Tfr 细胞共培养中的 Tfh/B 细胞增殖、IgM 产生和分化。 Tfr 细胞表达高水平的 TNFR2。 MR2-1 刺激改变了 Tfr 细胞的基因表达谱。 MR2-1可增强Tfr细胞的细胞增殖和Foxp3表达。 MR2-1刺激的Tfr细胞表达ICOS和程序性细胞死亡蛋白1，并显着抑制Tfh/B细胞增殖、IgM产生和B细胞分化。根据 CXCL13 梯度，TNFR2 刺激的 Tfr 细胞保留了迁移功能。总之，我们证明 TNFR2 刺激的 Tfr 细胞可以调节 Tfh 和 B 细胞。 TNF 抑制剂治疗期间抗体的异常产生可能至少部分与 Tfr 细胞中 TNFR2 信号传导抑制有关。此外，通过体外 TNFR2 刺激使 Tfr 细胞扩增和成熟可能有助于炎症和自身免疫性疾病的细胞治疗，以控制 GC 反应。
T follicular regulatory (Tfr) cells are a subset of CD4(+) T cells that express CXCR5 and migrate into germinal centers (GCs). They regulate GC reactions by communicating with T follicular helper (Tfh) and B cells. TNF inhibitors are used in inflammatory diseases; however, the generation of autoantibodies or anti-drug Abs sometimes causes problems. Because TNFR2 signaling is important for suppressive functions of regulatory T cells, we investigated the role of TNFR2 on human Tfr cells. Tfr cells stimulated with MR2-1 (an anti-TNFR2 agonistic Ab) were analyzed for cell proliferation, Foxp3 expression, and surface molecules. Tfh/B cell proliferation, IgM production, and differentiation in cocultures with MR2-1-stimulated Tfr cells were examined. Tfr cells express a high level of TNFR2. MR2-1 stimulation altered the gene expression profile of Tfr cells. Cell proliferation and Foxp3 expression of Tfr cells were enhanced by MR2-1. MR2-1-stimulated Tfr cells expressed ICOS and Programmed cell death protein 1 and significantly suppressed Tfh/B cell proliferation, IgM production, and B cell differentiation. TNFR2-stimulated Tfr cells retained the migration function according to the CXCL13 gradient. In conclusion, we showed that TNFR2-stiumulated Tfr cells can regulate Tfh and B cells. Aberrant antibody production during TNF inhibitor treatment might be, at least in part, associated with TNFR2 signaling inhibition in Tfr cells. In addition, expansion and maturation of Tfr cells via TNFR2 stimulation in vitro may be useful for a cell-based therapy in inflammatory and autoimmune diseases to control GC reactions.