In rheumatoid arthritis (RA), imbalanced T cells subsets play a critical role in sustaining chronic inflammatory responses in the synovium. Naïve T cells in RA patients undergo maldifferentiation, including an increase in the effector Th1/Th17 lineage and a reduction in regulatory T (Treg) cells. Upon stimulation, naïve CD4+CD45RO− T cells from RA patients exhibited insufficient expression of Foxp3, which induced a deficiency in Tregs production and an imbalance of Treg/Th17 differentiation. Further mechanistic study indicated that RA T cells failed to produce sufficient levels of the histone acetyltransferase Tip60, leading to reduced acetylation of Foxp3; this, in turn, decreased Foxp3 expression, impaired Treg commitment, and promoted Th17 production. Moreover, in human synovium chimeric mice, suppression of Tip60 activity in healthy T cells promoted tissue infiltration and arthritogenesis, while reconstitution of Tip60 in RA T cells suppressed synovitis and effector T cell infiltration. Our findings link T cell maldifferentiation and tissue infiltration with Tip60-mediated Foxp3 acetylation and identify Tip60 as a potential therapeutic target for suppression of tissue inflammation and autoimmunogenesis in RA. Image 1 • Acetyltransferase Tip60 expression is downregulated in the CD4+ T cells of RA patients. • CD4+ T cells in RA patients have an imbalanced state between Th17/Treg cells. • Tip60 insufficiency in CD4+ T of RA patients blocks Foxp3 acetylation, downregulates Foxp3 expression. • Tip60-Foxp3 insufficiency in CD4+ T of RA patients decreases Treg cell and increases Th17 cell differentiation. • Tip60-Foxp3 insufficiency induces T cell tissue infiltration and arthritogenesis in vivo. [ABSTRACT FROM AUTHOR]