CD4+ T cell affinity can affect gender bias, disease severity and B cell requirement in inflammatory arthritis. (60.6)

Abstract

Abstract CD4+ T cells make a crucial contribution to the development of inflammatory arthritis both in humans and in mouse models. However, how the affinity with which T cells recognize target antigens might shape disease development and influence treatment modalities is poorly understood. We have examined these phenomena in mouse models of autoimmune arthritis: TS1xHACII and TS1(SW)xHACII mice express influenza hemagglutinin (HA) as a neo-self peptide and co-express transgenic TCRs that have either high affinity (TS1xHACII) or low affinity (TS1(SW)xHACII) for the HA-derived MHCII determinant, S1. Despite extensive deletion of autoreactive TCRs, arthritis spontaneously develops in both strains and in each case arthritis can be prevented by IL-17 blockade. Notably, the low affinity model displays less severe extra-articular disease manifestations and a prominent female bias emerges. In addition, B cells are required for arthritis development in the low affinity setting; by contrast, B cells are not required in the high affinity setting where the disease is accompanied by higher levels of pro-inflammatory cytokines. These studies demonstrate that the overall affinity of the CD4+ T cell response to an autoantigen can play a prominent role in guiding the pathways to inflammatory arthritis development and presentation. These studies may also explain why treatment modalities targeting particular pathways (cytokines vs B cells) can exhibit different efficacies in arthritis patients.