Department of Internal Medicine, Yale University, New Haven, CT, USA.
Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
Cell Rep. 2020 Jun 30;31(13):107820. doi: 10.1016/j.celrep.2020.107820.
IRF5 polymorphisms are associated with multiple immune-mediated diseases, including ulcerative colitis. IRF5 contributions are attributed to its role in myeloid lineages. How T cell-intrinsic IRF5 contributes to inflammatory outcomes is not well understood. We identify a previously undefined key role for T cell-intrinsic IRF5. In mice, IRF5 in CD4 T cells promotes Th1- and Th17-associated cytokines and decreases Th2-associated cytokines. IRF5 is required for the optimal assembly of the TCR-initiated signaling complex and downstream signaling at early times, and at later times binds to promoters of Th1- and Th17-associated transcription factors and cytokines. IRF5 also regulates chemokine receptor-initiated signaling and, in turn, T cell migration. In vivo, IRF5 in CD4 T cells enhances the severity of experimental colitis. Importantly, human CD4 T cells from high IRF5-expressing disease-risk genetic carriers demonstrate increased chemokine-induced migration and Th1/Th17 cytokines and reduced Th2-associated and anti-inflammatory cytokines. These data demonstrate key roles for T cell-intrinsic IRF5 in inflammatory outcomes.
IRF5 多态性与多种免疫介导的疾病有关，包括溃疡性结肠炎。IRF5 的作用归因于其在髓系细胞中的作用。T 细胞内在的 IRF5 如何促进炎症反应尚不清楚。我们发现了 T 细胞内在的 IRF5 的一个以前未定义的关键作用。在小鼠中，CD4 T 细胞中的 IRF5 促进 Th1 和 Th17 相关细胞因子的产生，并减少 Th2 相关细胞因子的产生。IRF5 是 TCR 启动信号复合物和下游信号的最佳组装所必需的，在早期和晚期，IRF5 结合到 Th1 和 Th17 相关转录因子和细胞因子的启动子上。IRF5 还调节趋化因子受体启动的信号转导，进而调节 T 细胞的迁移。在体内，CD4 T 细胞中的 IRF5 增强了实验性结肠炎的严重程度。重要的是，来自高表达 IRF5 的疾病风险遗传携带者的人类 CD4 T 细胞显示出增加的趋化因子诱导的迁移和 Th1/Th17 细胞因子，减少 Th2 相关和抗炎细胞因子。这些数据表明 T 细胞内在的 IRF5 在炎症反应中起关键作用。
