DRB1*0402 may influence arthritis by promoting naive CD4+ T‐cell differentiation in to regulatory T cells

HLA-DRB1*0401 has been associated with predisposition to develop rheumatoid arthritis (RA) and collagen-induced arthritis (CIA) while *0402 is not associated with susceptibility. In this study, we determined if *0401 mice have CD4 T cell repertoire that is predetermined to produce proinflammatory cytokines. The data presented here shows that both *0401 and *0402 mice can produce TH1/TH17 cytokines although kinetics of response may be different. However, in the context of antigen-specific response in CIA, *0402 mice generate a TH2 response that may explain its resistance to develop arthritis. In addition, a significant subset of naive CD4 T cells when activated in polarizing conditions differentiate into T regulatory cells in *0402 mice that produce IFNγ. *0401 mice harbor memory CD4 T cells that differentiate in to IL-17+ cells in various conditions. We hypothesize that *0401 has been evolutionarily selected due to its ability to clear infection. Our data suggests that *0401 generates a strong immune response to LPS and may be efficient in clearing infection. Autoimmunity is a bystander effect of the cytokine storm that along with the presence of low number of T regulatory cells in *0401 mice ensues immune dysregulation.