E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases
Zijun Wang, … , Akihiko Yoshimura, Qianjin Lu
Zijun Wang, … , Akihiko Yoshimura, Qianjin Lu
Published March 19, 2020
Citation Information: J Clin Invest. 2020;130(7):3717-3733. https://doi.org/10.1172/JCI129018.
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E4BP4-mediated inhibition of T follicular helper cell differentiation is compromised in autoimmune diseases

Abstract

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.

Authors

Zijun Wang, Ming Zhao, Jinghua Yin, Limin Liu, Longyuan Hu, Yi Huang, Aiyun Liu, Jiajun Ouyang, Xiaoli Min, Shijia Rao, Wenhui Zhou, Haijing Wu, Akihiko Yoshimura, Qianjin Lu

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Figure 3

E4BP4 regulates Tfh cell differentiation in vitro.

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E4BP4 regulates Tfh cell differentiation in vitro. (A) Flow cytometric a...
(A) Flow cytometric analysis of CXCR5+PD-1+ in naive CD4+ T cells from the E4bp4-cKO and WT mice. Statistical analysis is indicated in B. (C–F) Flow cytometric analysis of in vitro–polarized Tfh-like cells from the E4bp4-cKO and WT mice and from the E4bp4-cKI and WT mice. Representative histograms of BCL6 and IL-21 expression in CD4+CXCR5+PD-1+ Tfh-like cells are shown in D and F (n = 6). (G) Gene set enrichment analysis of gene signatures (either upregulation or downregulation) in Tfh cells relative to their expression in non–Tfh cells from published data (GEO accession code GSE16697), and differentially expressed genes between the in vitro–polarized E4bp4-cKO Tfh-like cells and WT Tfh-like cells. Red/blue rectangles indicate enriched genes in the E4bp4-cKO Tfh-like cells. (H) RNA-seq analysis of gene expression of in vitro–polarized Tfh-like cells; colors indicate upregulated (red) or downregulated (blue) genes. (I) Clustered heatmap of 39 Tfh signature genes regulated by E4BP4. (J) Clustered heatmap of 10 Tfr signature genes regulated by E4BP4. The data were normalized from 2 replicates (n = 2). Genes with the most transcriptional changes are listed. (A–F) Data are representative of 3 independent experiments. Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.