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^midCD4⁺ effector memory T cell subset that expands with age, which we designated "age-associated T helper (T_HA) cells." T_HA 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_HA cells, gene expression in T_HA 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_HA cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of T_HA cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.