The Shc family protein adaptor, Rai, acts as a negative regulator of Th17 and Th1 cell development

Rai, a Shc adapter family member, acts as a negative regulator of antigen receptor signaling in T and B cells. Rai^-/- mice develop lupus-like autoimmunity associated to the spontaneous activation of self-reactive lymphocytes. Here, we have addressed the potential role of Rai in the development of the proinflammatory Th1 and Th17 subsets, which are centrally implicated in the pathogenesis of a number of autoimmune diseases, including lupus. We show that Rai^-/- mice display a spontaneous Th1/Th17 bias. In vitro polarization experiments on naive and effector/memory CD4⁺+ T cells demonstrate that Rai^-/- favors the development and expansion of Th17 but not Th1 cells, indicating that Rai modulates TCR signaling to antagonize the pathways driving naive CD4⁺⁺ T cell differentiation to the Th17 lineage, while indirectly limiting Th1 cell development in vivo. Th1 and Th17 cell infiltrates were found in the kidneys of Rai^-/- mice, providing evidence that Rai^-/- contributes to the development of lupus nephritis, not only by enhancing lymphocyte activation but also by promoting the development and expansion of proinflammatory effector T cells. Interestingly, T cells from SLE patients were found to have a defect in Rai expression, suggesting a role for Rai in disease pathogenesis.