Age-associated CD4 + T cells with B cell–promoting functions are regulated by ZEB2 in autoimmunity

Aging is a significant risk factor for autoimmunity, and many autoimmune diseases tend to onset during adulthood. We conducted an extensive analysis of CD4 + T cell subsets from 354 patients with autoimmune disease and healthy controls via flow cytometry and bulk RNA sequencing. As a result, we identified a distinct CXCR3 mid CD4 + effector memory T cell subset that expands with age, which we designated “age-associated T helper (T H A) cells.” T H A cells exhibited both a cytotoxic phenotype and B cell helper functions, and these features were regulated by the transcription factor ZEB2. Consistent with the highly skewed T cell receptor usage of T H A cells, gene expression in T H A cells from patients with systemic lupus erythematosus reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that T H A cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of T H A cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.