E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases

• Published in: The Journal of clinical investigation 2020-07, Vol.130 (7), p.3717-3733
• Main Authors: Wang, Zijun, Zhao, Ming, Yin, Jinghua, Liu, Limin, Hu, Longyuan, Huang, Yi, Liu, Aiyun, Ouyang, Jiajun, Min, Xiaoli, Rao, Shijia, Zhou, Wenhui, Wu, Haijing, Yoshimura, Akihiko, Lu, Qianjin
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Autoimmune diseases; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - immunology; Bcl-6 protein; Biomedical research; Cell activation; Cell differentiation; Cell Differentiation - genetics; Cell Differentiation - immunology; Cytokines; Disease; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - immunology; Epigenetic inheritance; Female; Gene expression; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - immunology; Humans; Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lymphatic system; Lymphocytes; Lymphocytes T; Male; Medical research; Mice; Mice, Knockout; Molecular modelling; Phosphorylation; Protein binding; Proteins; Proto-Oncogene Proteins c-bcl-6 - genetics; Proto-Oncogene Proteins c-bcl-6 - immunology; Scientific equipment industry; Systemic lupus erythematosus; T cells; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - pathology; Transcription factors
• ISSN: 0021-9738; 1558-8238
• 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.