Ablation of PDIA3 attenuates rheumatoid arthritis by restraining Th1 and Th17 polarization program

Abstract Rheumatoid arthritis (RA) is characterized by the chronic synovial inflammation and bone destruction, which eventually cause joint deformity along with physical disability. Aberrant autoimmune T cell activation underpins RA pathogenesis, but the molecular cues that boost autoimmune T cell program remain elusive. Herein, we report that protein disulfide-isomerase A3 (PDIA3) serves as a critical intrinsic regulator to orchestrate Th1 and Th17 differentiation in RA setting. PDIA3 was remarkably upregulated in CD4 T cells in arthritic mice and positively correlated with key clinic parameters including C-reactive protein (CRP) and Disease Activity Scores 28 (DAS28) in RA patients. Depletion of Pdia3 in CD4 T cells protected mice against RA induction, while CD4 T cells deficient in Pdia3 were featured by the attenuated Th1 and Th17 polarization. Mechanistically, synovial fibroblasts (SFs) derived Wnt5a acts on CD4 T cells to enhance NFAT activity; then, NFAT directly binds to the Pdia3 promoter to facilitate its transcription. Intriguingly, PDIA3 did not exert its function in the endoplasmic reticulum (ER) of CD4 T cells, rather bolstered Th1 and Th17 program mainly through forming a complex with either STAT1 or PKM2 in the nucleus, by which it acted as a transcription coactivator. In accordance, pharmacological inhibition of PDIA3 attenuated collagen-induced arthritis in mice. Collectively, our data unveiled a positive feedback loop in the synovial niche where highly expressed PDIA3 promotes pathogenic CD4 T cell polarization during RA pathogenesis, and targeting PDIA3 to block the crosstalk between SFs and CD4 T cells could be a viable strategy against RA.