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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 1

E4BP4 is more abundantly expressed in Tfh cells.

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E4BP4 is more abundantly expressed in Tfh cells.
(A) Analysis of naive C...
(A) Analysis of naive CD4+ T cells from 8-week-old C57BL/6 mice stimulated in vitro under Th0, Th1, Th2, Th17, Treg, and Tfh cell–polarizing conditions for 3 days (Th0, Th1, Th17, Treg, and Tfh cells) or 5 days (Th2 cells) by flow cytometry for mean fluorescence intensity (MFI) of E4BP4 (n = 9). (B) mRNA expression of E4bp4 in T cell subsets indicated in A (n = 6). (C) Naive CD4+ T cells, anti-CD3/CD28–activated CD4+ T cells, and in vitro–polarized Tfh cells were stained by anti-E4BP4 (red) and DAPI (blue) and analyzed by confocal microscopy. Scale bar: 5 μm. (D) Statistical intensity of E4BP4 in nuclei (n = 6). (E) Flow cytometric analysis of E4BP4 expression in mice CD4+ T cells (n = 10). (F) Gating strategy of CXCR5+PD-1+(Tfh) or CXCR5–PD-1– (non-Tfh) cell phenotype in CD4+ T cells from KLH immunized C57BL/6 mice. Analysis of E4BP4 and BCL6 expression (MFI) is shown in the right panel. (G) Statistical analysis of F (n = 10). (H) Gating strategy of human tonsillar CD45RO+ memory/effector or CD45RO– naive CD4+ T cells. CD45RO+ cells were subsequently divided into CXCR5lo, CXCR5int, and CXCR5hi gates. (I and J) Representative histograms of CXCR5, BCL6, PD-1, and E4BP4 MFI expressions in subsets outlined in H (n = 10). Data are representative of 3 independent experiments. For A, B, D, and J, 1-way ANOVA with Dunnett’s post hoc test, E and G with Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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