CD20+ T follicular helper–like cells drive antigen-specific autoimmunity in bullous pemphigoid
Hui Fang, Shengxian Shen, Kang Li, Tianyu Cao, Bing Wang, Haijun Miao, Ke Xue, Yaxing Bai, Liang Li, Xia Li, Pei Qiao, Jieyu Zhang, Huanhuan Qu, Chen Zhang, Chunying Xiao, Bingyu Pang, Meng Fu, Hongjiang Qiao, Shuai Shao, Erle Dang, Gang Wang
Hui Fang, Shengxian Shen, Kang Li, Tianyu Cao, Bing Wang, Haijun Miao, Ke Xue, Yaxing Bai, Liang Li, Xia Li, Pei Qiao, Jieyu Zhang, Huanhuan Qu, Chen Zhang, Chunying Xiao, Bingyu Pang, Meng Fu, Hongjiang Qiao, Shuai Shao, Erle Dang, Gang Wang
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Research Article Autoimmunity Dermatology

CD20+ T follicular helper–like cells drive antigen-specific autoimmunity in bullous pemphigoid

Abstract

CD20+ T cells are increasingly recognized as drivers of autoimmune and inflammatory diseases. However, their origin, development, and specific role in autoimmune skin diseases remain poorly understood. In this study, we observed an expansion of CD20+ T cells in the peripheral blood and skin lesions of patients with bullous pemphigoid (BP), which correlated with the levels of pathogenic autoantibodies and disease severity. Compared with CD20– T cells, CD20+ T cells exhibited enhanced metabolic and pro-inflammatory activities. In particular, antigen-specific BP180-NC16A–reactive T cells were enriched within the CD4+CD20+ subset. In both patients with BP and BP180-immunized mice, CD4+CD20+ T cells exhibited an antigen-specific T follicular helper–like phenotype, facilitating antibody production and B cell differentiation, whereas CD8+CD20+ T cells displayed cytotoxic and pro-inflammatory features. Mechanistically, we found that expression of the CD20-encoding gene MS4A1 in T cells was regulated by transcription factor PAX5 in a DNA methylation–dependent manner. Therefore, our study elucidates the regulatory mechanisms governing CD20+ T cells and highlights their important role in the pathogenesis of BP.

Authors

Hui Fang, Shengxian Shen, Kang Li, Tianyu Cao, Bing Wang, Haijun Miao, Ke Xue, Yaxing Bai, Liang Li, Xia Li, Pei Qiao, Jieyu Zhang, Huanhuan Qu, Chen Zhang, Chunying Xiao, Bingyu Pang, Meng Fu, Hongjiang Qiao, Shuai Shao, Erle Dang, Gang Wang

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Figure 7

The transcription factor PAX5 regulates endogenous CD20 expression in human CD20+ T cells.

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The transcription factor PAX5 regulates endogenous CD20 expression in hu...
(A) Heatmap showing the top differentially expressed transcription factors between CD3+CD20– T cells and CD3+CD20+ T cells. (B) Motifs resembling PAX5-binding motifs within the MS4A1 regulatory region. (C) Luciferase activities of wild-type MS4A1 and MS4A1 with a PAX5–binding site mutation were determined via luciferase reporter assays in HEK293T cells (n = 6). (D) Bulk RNA-seq analysis of PAX5 expression in FACS-sorted CD19+ B cells, CD3+CD20– T cells, and CD3+CD20+ T cells from Con and patients with BP (n = 3). (E) Representative immunofluorescence images showing PAX5 (green), CD3 (red), and CD20 (yellow) in sorted human CD3+CD20+ T cells, CD3+CD20– T cells, and CD19+ B cells (n = 3). Scale bar = 5 μm. (F) PAX5 mRNA expression in NC-KO or PAX5-knockout (PAX5-KO) T cells following activated with anti-CD3/CD28 Dynabeads (n = 4). (G) Frequencies of CD4+CD20+ T cells among control or PAX5-KO T cells (n = 4). (H) Frequencies of CXCR5+PD-1+ T cells within CD4+ T cells among control or PAX5-KO T cells (n = 4). (I) MFI of IL-21 in CD4+ T cells among control or PAX5-KO T cells (n = 4). All data are presented as the mean ± SD. One-way ANOVA with Tukey’s post hoc test was used for D. An unpaired 2-tailed Student’s t test was used for C and F–I. *P < 0.05, **P < 0.01, ***P < 0.001.