Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institute of Health, Bethesda, MD 20892, USA.
Department of Immunology, Jeonbuk National University Medical School, Jeonju, Jeonbuk 54907, Korea.
Int J Mol Sci. 2021 Mar 9;22(5):2775. doi: 10.3390/ijms22052775.
Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.
干扰素调节因子 4（IRF4）和 IRF8 调节淋巴样和髓样细胞的分化、生长和功能。靶向敲除 T 细胞中的（CD4-IRF8KO）已被证明可加重结肠炎和实验性自身免疫性葡萄膜炎（EAU），这是人类葡萄膜炎的小鼠模型。因此，我们生成了 T 细胞中缺失（CD4-IRF4KO）的小鼠，并研究了 T 细胞中 IRF4 的表达是否也需要调节抑制自身免疫疾病的 T 细胞。令人惊讶的是，我们发现 CD4-IRF4KO 小鼠对 EAU 具有抗性。抑制 EAU 的部分原因是抑制了 Th17 细胞的致病性反应，同时诱导了在眼部和外周淋巴组织中分泌 IL-10 和/或 IL-35 的调节性淋巴细胞的扩张。此外，CD4-IRF4KO T 细胞表现出细胞代谢的改变，并在两个 Ikaros 锌指（IKZF）转录因子（Ikaros、Aiolos）的表达上存在缺陷，这些因子是淋巴细胞分化、代谢和细胞命运决定所必需的。因此，IRF4 和 IkZF 的协同作用可能诱导分化淋巴细胞的代谢重编程，从而动态调节介导葡萄膜炎中免疫病理机制的 T 和 B 淋巴细胞亚群的相对丰度。此外，IRF4 和 IRF8 在 EAU 中的截然相反的作用表明，IRF4 在 T 细胞中的固有功能可能是激活促炎反应，而 IRF8 则促进免疫抑制机制的扩张。
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