The pathogenic role of CD4+ tissue-resident memory T cells bearing Tfh-like phenotype in pemphigus lesions.

In the skin lesions of pemphigus, a group of life-threatening autoimmune bullous diseases, an overrepresentation of CD4+ tissue-resident memory T (TRM) cells was found. We sought to investigate the contributions of CD4+ TRM cells to the severity and refractoriness of pemphigus and their role in local immunological pathogenesis. Our data showed that CD4+ TRM cells accumulated significantly in pemphigus skin lesions. These CD4+ TRM cells expressed a specific set of T follicular helper (Tfh) cell-related costimulatory molecules. We also found that CD4+ TRM cells remaining in lesions produced IL-17A and IL-21. In vitro, CD4+ TRM cells exhibited strong support and assistance to autoantibody production. Through transcriptomic sequencing and bioinformatics analysis, we identified that the transcription factor interferon regulatory factor 4 (IRF4) was responsible for IL-21 overexpression and autoantibody production. Our results demonstrated that Tfh-like CD4+ TRM cells in pemphigus lesions promoted local autoantibody production, resulting in the formation and recurrence of lesions, which supports targeting this cell subset in pemphigus. IRF4 might serve as a potential therapeutic target.