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

Objective Rai 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. Materials and methods Lymph node T cells or naïve T cells were isolated from wild-type and Rai-/- mice and their cytokine profile was determined by ELISPOT and qRT-PCR both as such and after stimulation in vitro with immobilized anti-CD3 mAb in the presence or absence of polarizing cytokines. The expression of rai was measured in PBL from SLE patients and healthy donors by qRT-PCR. Results We show that Rai-/- mice display a spontaneous Th1/Th17 bias. In vitro polarization experiments demonstrate that rai deficiency favours 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. Th1 and Th17 cell infiltrates were found in the kidneys of Rai-/- mice, providing evidence that Rai deficiency 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. Conclusions We have identified Rai as a negative regulator of Th17 cell differentiation and expansion in the mouse and found evidence of an impairment of Rai expression in PBL from SLE patients.