Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, China.
Research Unit of Key Technologies of Diagnosis and Treatment for Immune-related Skin Diseases, Chinese Academy of Medical Sciences, Changsha, China.
J Clin Invest. 2020 Jul 1;130(7):3717-3733. doi: 10.1172/JCI129018.
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 Bcl6 transcription by recruiting the repressive epigenetic modifiers HDAC1 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.
滤泡辅助 T 细胞（Tfh）对于生发中心（GC）反应的形成是不可或缺的，而滤泡辅助调节性 T 细胞（Tfr）则抑制 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]）的发病机制中起着重要作用。然而，减轻过度 Tfh 细胞分化的分子机制尚未完全阐明。本研究证明，腺病毒 E4 启动子结合蛋白（E4BP4）介导反馈回路并作为转录制动器抑制 Tfh 细胞分化。此外，我们还发现，SLE 患者的这种免疫机制受损。在 T 细胞中建立条件性敲除（cKO）或敲入（cKI）E4bp4 基因的小鼠表明，E4BP4 强烈抑制 Tfh 细胞分化。从机制上讲，E4BP4 通过招募抑制性表观遗传修饰剂 HDAC1 和 EZH2 来调节 Bcl6 转录。E4BP4 磷酸化位点突变体在抑制 Tfh 细胞分化方面的能力有限。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，其功能受损与 SLE 中不受控制的自身免疫反应有关。
