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

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.