E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases
E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases
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E4BP4介导的滤泡辅助T细胞分化抑制在自身免疫性疾病中受到损害
DOI：
10.1172/jci129018
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发表时间：
2020-07-01
影响因子：
15.9
通讯作者：
Lu, Qianjin
中科院分区：
文献类型：
--
作者：
Wang, Zijun;Zhao, Ming;Lu, Qianjin
滤泡辅助性T细胞（Tfh）是生发中心（GC）反应形成所必需的，而滤泡调节性T细胞（Tfr）抑制Tfh介导的GC反应。Tfh细胞的异常激活在自身免疫性疾病如系统性红斑狼疮（SLE）的发病机制中起重要作用。然而，减轻过度Tfh细胞分化的分子机制尚未完全理解。在此，我们证明腺病毒E4启动子结合蛋白（E4BP4）介导的反馈回路，并作为转录制动器，以抑制Tfh细胞分化。此外，我们表明，这样的免疫机制在SLE患者中受到损害。在T细胞中建立具有E4bp4基因的条件性敲除（cKO）或敲入（cKI）的小鼠揭示了E4BP4强烈抑制Tfh细胞分化。在机制上，E4BP4通过募集抑制性表观遗传修饰物HDACT和EZH2来调节BcI6转录。E4BP4磷酸化位点突变体抑制Tfh细胞分化的能力有限。在SLE中，我们检测到E4BP4磷酸化受损，发现这种受损的转录因子与疾病活动呈正相关。这些发现揭示了E4BP4抑制Tfh细胞分化的分子机制，Tfh细胞的功能受损与SLE中不受控制的自身免疫反应相关。
T follicular helper (Tfh) cells are indispensable for the formation of germinal center (GC) reactions, whereas T follicular regulatory (Tfr) cells inhibit Tfh-mediated GC responses. Aberrant activation of Tfh cells contributes substantially to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). Nonetheless, the molecular mechanisms mitigating excessive Tfh cell differentiation are not fully understood. Herein we demonstrate that the adenovirus E4 promoter-binding protein (E4BP4) mediates a feedback loop and acts as a transcriptional brake to inhibit Tfh cell differentiation. Furthermore, we show that such an immunological mechanism is compromised in patients with SLE. Establishing mice with either conditional knockout (cKO) or knockin (cKI) of the E4bp4 gene in T cells reveals that E4BP4 strongly inhibits Tfh cell differentiation. Mechanistically, E4BP4 regulates BcI6 transcription by recruiting the repressive epigenetic modifiers HDACT and EZH2. E4BP4 phosphorylation site mutants have limited capability with regard to inhibiting Tfh cell differentiation. In SLE, we detected impaired phosphorylation of E4BP4, finding that this compromised transcription factor is positively correlated with disease activity. These findings unveiled molecular mechanisms by which E4BP4 restrains Tfh cell differentiation, whose compromised function is associated with uncontrolled autoimmune reactions in SLE.