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

<jats:title>Abstract</jats:title> <jats:p>Rai prevents lupus nephritis by impairing the development and expansion of both proinflammatory Th17 and Th1 cells.</jats:p> <jats:p>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.</jats:p>