Aire attenuate collagen-induced arthritis by suppressing T follicular helper cells through ICOSL

To assess the expression levels of autoimmune regulator (Aire) and inducible costimulator molecule ligand (ICOSL), as well as T follicular helper (Tfh) cell numbers in rheumatoid arthritis (RA) patients, and to explore their relationship with RA severity. We also aimed to investigate the effect of Aire on arthritis and its underlying mechanisms. The expression levels of Aire, ICOSL, and Tfh cell numbers were measured in RA patients. The relationship between these factors and the levels of anticyclic citrullinated peptide antibodies (Anti-CCP) as well as the Disease Activity Score in 28 joints (DAS28) was analyzed. To investigate the effect of Aire on arthritis, Aire-overexpressing bone marrow-derived dendritic cells (Aire-BMDCs) and recombinant ICOSL were transferred into collagen-induced arthritis (CIA) mice, the symptoms, clinical scores, anti-collagen type II antibodies (anti-CII Abs), rheumatoid factor (RF), proportions of Tfh cells, and percentages of germinal center (GC) B cells in CIA mice were examined. The results showed that Aire levels were significantly decreased in CD14+ PBMCs from patients with RA, and there were negative correlations between ICOSL expression levels, Tfh cell numbers, and Aire expression. Additionally, these factors were correlated with Anti-CCP levels and DAS28. Aire-BMDCs could influence Tfh differentiation, GC B cell development, as well as the levels of anti-CII Abs and RF, which further alleviate the symptoms and reduce clinical scores partly through ICOSL in CIA mice. The findings suggest that Aire may alleviate rheumatoid arthritis by inhibiting ICOSL, which further inhibits Tfh cell differentiation and autoantibody production.