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 autoimmune disease patients 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 helper T (ThA) cells". ThA 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 ThA cells, gene expression in ThA cells from systemic lupus erythematosus patients reflected disease activity and was affected by treatment with a calcineurin inhibitor. Moreover, analysis of single-cell RNA sequencing data revealed that ThA cells infiltrate damaged organs in patients with autoimmune diseases. Together, our characterization of ThA cells may facilitate improved understanding of the relationship between aging and autoimmune diseases.