Impaired Tip60-mediated Foxp3 acetylation attenuates regulatory T cell development in rheumatoid arthritis. (June 2019)

• Record Type: Journal Article
• Authors: Su, Qiao; Jing, Jun; Li, Wuguo; Ma, Jianda; Zhang, Xueling; Wang, Zongren; Zhou, Zhongyang; Dai, Lie; Shao, Lan
• Is Part Of: Journal of autoimmunity. Volume 100(2019)
• Page Start: 27
• Page End: 39
• Publication Date: 2019-06
• Subjects: Tip60 -- Foxp3 -- Acetylation -- T cell differentiation -- Rheumatoid arthritis; RA Rheumatoid arthritis -- Treg Regulatory T cell -- MYST Mof–Ybf2–Sas2–Tip60 -- TCR T cell receptor -- PBMCs Peripheral blood mononuclear cells -- SLE Systemic erythematosus lupus -- ACR American college of rheumatology -- SDS-PAGE Sodium dodecyl sulfate–polyacrylamide gel electrophoresis -- RIPA Radioimmunoprecipitation -- DAS-28 Disease activity score-28 -- MFI Mean fluorescence intensity -- TRB T cell receptor beta locus -- RANKL Receptor activator of nuclear factor κappa B ligand -- ESR Erythrocyte sedimentation rate -- DMARDs Disease-modifying antirheumatic drugs; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2019.02.007
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: 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 .