Epigenomic insights into CD4+ T-cell–mediated pathogenesis in autoimmune diseases

T cells are central mediators of autoimmune disease pathogenesis. After developing in the thymus, T cells undergo diverse differentiation programs and acquire specialized effector functions in inflamed tissues. Despite sharing the same genome, T cells adopt diverse phenotypes and functions, highlighting the importance of epigenetic mechanisms in regulating their differentiation and activity; however, these mechanisms remain incompletely understood. Comprehensive epigenetic analyses are therefore essential to elucidate these processes. To date, a wide range of approaches has been applied to T-cell research, including analyses of DNA methylation, histone modifications, chromatin accessibility, transcription factor binding, and three-dimensional chromatin architecture. More recently, rapid advances in single-cell technologies have enabled simultaneous profiling of gene expression and chromatin accessibility in the same cell. In parallel, CRISPR-based approaches have enabled genome-wide functional interrogation in primary human T cells, including analyses of non-coding regulatory regions. Furthermore, epigenomic approaches are now being applied to spatial analyses and are expected to provide deeper insight into the organization of T-cell states in inflamed tissues. In this mini review, we highlight recent studies that have leveraged these cutting-edge technologies and discuss how they are advancing our understanding of the T-cell–mediated pathogenesis of autoimmune diseases.