Impaired Tip60-mediated Foxp3 acetylation attenuates regulatory T cell development in rheumatoid arthritis

• Published in: Journal of autoimmunity 2019-06, Vol.100, p.27-39
• Main Authors: Su, Qiao, Jing, Jun, Li, Wuguo, Ma, Jianda, Zhang, Xueling, Wang, Zongren, Zhou, Zhongyang, Dai, Lie, Shao, Lan
• Format: Article
• Language: English
• Subjects: Acetylation; Foxp3; Rheumatoid arthritis; T cell differentiation; Tip60
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2019.02.007

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. [Display omitted] •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.