Altered balance of helper T cells in Rai-/- mice

Objective: A number of immune related pathologies, such as autoimmune and allergic disorders, develop as the result of an imbalance among Th subsets. A Th1 bias has been consistently observed in autoimmunity both in man and in mouse, which has led to the notion that autoimmunity is a disease initiated by an abnormal polarization of CD4+ T cells towards the proinflammatory Th1 lineage. In addition to Th1 and Th2 cells, a third subset of effector Th cells producing IL-17 has recently been described and termed Th17. Th17 cells have been causally associated to the pathogenesis of human autoimmune diseases, of which multiple sclerosis is a striking example. Recent data have identified molecular adaptors as master regulators not only of T-cell activation, but also of Th cell development, highlighting these molecules as attractive targets for pharmacological manipulation. We have recently demonstrated that loss of Rai, a member of the Shc family expressed both in neuronal and in T cells, results in the development of systemic autoimmunity (Savino et al 2009). Since peripheral T cells from Rai -/- mice show an up-regulation of the Th17 cytokines we addressed the potential role of Rai in the signaling pathways controlling Th17 development and in the pathogenesis of multiple sclerosis. Methods: To evaluate the potential role of Rai in the signaling pathways controlling Th17 development, T cells isolated from wild-type and Rai-/- mice have been analyzed as such or following in vitro stimulation with agonistic anti-CD3 mAb in combination with polarizing cytokines or not for the expression of cytokines and transcription factors diagnostic of the Th1, Th2 and Th17 subsets. The impact of Rai on signaling pathways activated by the TCR when coengaged with the receptors responsible for Th17 commitment have also been analyzed. The susceptibility of Rai-/- mice to develop EAE was assessed by using MOG as immunogen. Results: Our results indicate that Rai interferes with Th17 development by altering key steps of the signaling pathways triggered by TCR in combination with TGFβ and IL-6 and alter the severity of EAE disease.