Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; and.
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Tohoku University, Sendai, Japan.
J Immunol. 2022 Feb 1;208(3):642-650. doi: 10.4049/jimmunol.2001358. Epub 2022 Jan 7.
TNF receptor-associated factor 5 (TRAF5) restrains early signaling activity of the IL-6 receptor in naive CD4 T cells by interacting with the shared gp130 chain, although TRAF5 was initially discovered as a cytoplasmic adaptor protein to activate signaling mediated by TNF receptor family molecules. This leads to the question of whether TRAF5 limits signaling via the receptor for IL-27, which is composed of gp130 and WSX-1. The aim of this study is to clarify the role of TRAF5 in IL-27 receptor signaling and to understand the differential role of TRAF5 on cytokine receptor signaling. We found that CD4 T cells displayed significantly higher levels of phosphorylated STAT1 and STAT-regulated genes and , as early as 1 h after IL-27 exposure when compared with CD4 T cells. Upon IL-27 and TCR signals, the deficiency significantly increased the induction of IL-10 and promoted the proliferation of CD4 T cells. mice injected with IL-27 displayed significantly enhanced delayed-type hypersensitivity responses, demonstrating that TRAF5 works as a negative regulator for IL-27 receptor signaling. In contrast, IL-2 and proliferation mediated by glucocorticoid-induced TNF receptor-related protein (GITR) and TCR signals were significantly decreased in CD4 T cells, confirming that TRAF5 works as a positive regulator for cosignaling via GITR. Collectively, our results demonstrate that TRAF5 reciprocally controls signals mediated by the IL-27 receptor and GITR in CD4 T cells and suggest that the regulatory activity of TRAF5 in gp130 is distinct from that in TNF receptor family molecules in a T cell.
肿瘤坏死因子受体相关因子 5（TRAF5）通过与共享的 gp130 链相互作用来抑制幼稚 CD4 T 细胞中 IL-6 受体的早期信号活性，尽管 TRAF5 最初被发现为一种细胞质衔接蛋白，可激活 TNF 受体家族分子介导的信号。这就提出了一个问题，即 TRAF5 是否限制了由 gp130 和 WSX-1 组成的 IL-27 受体的信号转导。本研究旨在阐明 TRAF5 在 IL-27 受体信号转导中的作用，并了解 TRAF5 在细胞因子受体信号转导中的差异作用。我们发现，与幼稚 CD4 T 细胞相比，CD4 T 细胞在暴露于 IL-27 后仅 1 小时就显示出更高水平的磷酸化 STAT1 和 STAT 调节基因和。在 IL-27 和 TCR 信号的作用下，缺陷显著增加了 IL-10 的诱导，并促进了 CD4 T 细胞的增殖。用 IL-27 注射的小鼠显示出明显增强的迟发型超敏反应，表明 TRAF5 作为 IL-27 受体信号的负调节剂起作用。相反，IL-2 和糖皮质激素诱导的 TNF 受体相关蛋白（GITR）和 TCR 信号介导的增殖在 TRAF5 缺陷型 CD4 T 细胞中显著降低，证实 TRAF5 作为 GITR 共信号的正调节剂起作用。总之，我们的结果表明，TRAF5 在 CD4 T 细胞中相互调节 IL-27 受体和 GITR 介导的信号，并表明 TRAF5 在 gp130 中的调节活性与 TNF 受体家族分子在 T 细胞中的调节活性不同。
