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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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Research Article Autoimmunity Article has an altmetric score of 4

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

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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 4

E4BP4 deficiency promotes antigen-specific GC responses.

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E4BP4 deficiency promotes antigen-specific GC responses.
Age-matched WT ...
Age-matched WT or E4bp4-cKO mice were immunized with KLH for 14 days, then lymph node and spleen cells were harvested. (A and B) Flow cytometric analysis of FoxP3+ Treg cells, CD4+CXCR5+PD-1+ Tfh cells, and FoxP3+ Tfr cells in follicular T cells. (C) Analysis of B220+Fas+GL-7+ GC B cells. (D) Summary of the percentage of FoxP3+ Treg cells, Tfh cells, and FoxP3+ Tfr cells in follicular T cells, as described in A and B, and GC B cells, as described in C. (E) Immunofluorescence of GCs from WT and E4bp4-cKO mice, representative images of CD3 and PNA staining of LNs. Scale bars: 200 μm. Quantification of PNA+ GC areas and number of PNA+ follicles per lymph node. (F) Detection of serum anti-KLH–specific IgG1, IgG2a, IgG2b, IgG3, and IgM by ELISA. (G) Draining lymph node cells were restimulated with KLH for 3 days, and supernatant IL-21 expression was detected by ELISA. (H) Il21 and Bcl6 mRNA expression levels were analyzed by qPCR (n = 6). Data are representative of 4 independent experiments. Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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