FCRL3 modulates the function of human thymic regulatory T cells

Abstract

Abstract Peripheral tolerance is achieved as the result of a delicate balance between inflammatory and tolerogenic signals. Regulatory T cells (Treg) are at the forefront in maintaining this balance, and external factors capable of modifying their suppressive function can be a powerful tool in future therapies for cancer and autoimmune disease. FCRL3 is a member of a novel family of antibody binding receptors expressed by specific human B cell and thymic Treg (tTreg) subsets that are reported to have altered suppressive function. Most importantly, overexpression of FCRL3 is strongly associated various autoimmune diseases. In particular, FCRL3 overexpression on Tregs is associated with more severe cases of rheumatoid arthritis. FCRL3 in B cells was shown to have dual signaling capacity; however no study addressed the functional role of FCRL3 in Treg. We used tTregs purified from human blood and pre-stimulated through FCRL3 to directly test the role of FCRL3 on Treg function using in vitro Treg suppression assays. We observed that engagement of FCRL3 increased Treg proliferation while reduced their suppressive activity, suggesting for the first time a direct link between FCRL3 and Treg function. TLR2 signaling has also been shown to repress the suppressive effect of human Tregs, therefore we tested possible integration with FCRL3 signaling. When TLR2 agonists were used together with FCRL3 pre-stimulation, we found indications of signal integration by tTreg downstream of FCRL3 and microbial sensing. We propose that FCRL3 is a novel regulator of Treg functionality, suggesting a mechanism for its association with autoimmune diseases.