The influence of CD4+ T cell affinity for self-antigen on the development of inflammatory arthritis

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 T cells bearing autoreactive TCRs, arthritis spontaneously develops in both strains. In TS1xHACII mice, males and females develop arthritis equally. CD4+ T cells in this setting display high reactivity to the S1 self-antigen and disease is accompanied by high levels of pro-inflammatory cytokines. Arthritis was found to develop by a B cell-independent mechanism in TS1xHACII mice, although it can be suppressed by anti-IL-17 and anti-TNF treatments, the latter which prevented the accumulation of effector CD4+IL-17+ cells in the joints of treated mice. By contrast, arthritis develops with a significant female bias in the context of a more weakly autoreactive CD4+ T cell response in TS1(SW)xHACII mice and disease was accompanied by lower levels of inflammatory cytokines. IL-17 is also required for disease development in this setting as well; B cells, in this case however, were found to play a prominent role in disease pathogenesis. Rather than acting as a source of arthritogenic autoantibodies, B cells appear to serve as APCs to promote the formation of autoreactive CD4+ effector T cells (including Th17 cells). Unlike in TS1xHACII mice, anti-TNF treatment appears to modulate disease severity but was insufficient to ameliorate the onset of disease in TS1(SW)xHACII mice. These studies demonstrate that variations in the CD4 + T cell response to a single target autoantigen can play a prominent role in guiding the pathways to inflammatory arthritis development. These studies may also explain why treatment modalities targeting particular pathways (cytokines vs B cells) can exhibit different efficacies in arthritis patients