Methyl-CpG-binding domain protein 3 (MBD3) is an essential component of the nucleosome remodeling and deacetylase (NuRD) complex for chromatin remodeling. This study shows that T cell-specific deficiency of MBD3 produces severe multiorgan autoimmune diseases. Genome-wide transcriptome and epigenome profiling revealed that the MBD3 deficiency notably affected the activation of the Treg-specific enhancer of the Il2ra (CD25) gene. This results in reduced CD25 expression in thymic Treg precursors, and the consequent Treg cell deficiency due to high IL-2/CD25 dependency of thymic differentiation of Treg cells, but not that of conventional T cells. The results illustrate how epigenetic anomalies or variations in thymic T cell development can be causative of autoimmune and other immunological diseases through predominantly affecting Treg cell differentiation.(online publishing in Proceedings of the National Academy of Sciences of the United States of America on Oct. 15, 2026)

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Experimental Immunology