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

Abstract

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.

The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis

“…2D). Hence, consistent with our previous report (22), the encephalitogenic Th17 cell response was enhanced in the absence of Rai, ruling out the possibility that the milder EAE disease in Rai 2/2 mice could be accounted for by either a reduced generation of MOG-specific Th17 cells or their reduced infiltration into the CNS. and MOG-specific T cell lines were derived from splenocytes by in vitro stimulation with MOG peptide and subsequently expanded by restimulation with autologous bone marrow-derived DC in the presence of MOG .…”

“…This increase in IL-6 expression was higher when astrocytes were treated with supernatants from Rai 2/2 MOG-specific T cells and was largely reversed when a neutralizing anti-IL-17 mAb was added to the culture supernatants (Fig. 5A), consistent with the Th17 bias of Rai-deficient T cells (22) and the known ability of IL-17 to promote IL-6 production by astrocytes (34). When Rai 2/2 astrocytes were analyzed under the same conditions, their response to treatment with the conditioned supernatants was significantly lower when compared with Rai +/+ astrocytes, but was similarly dependent on IL-17 (Fig.…”

“…Conversely, mice deficient of either the phosphatase JKAP/DUSP22, which has been demonstrated to inactivate Lck by dephosphorylating Y394 (41), or the MAPK phosphatase DUSP14 (42) are more susceptible to EAE. In this work, we provide evidence that the adaptor Rai, which we have identified as a negative regulator of TCR signaling downstream of Lck (43), as well as of Th17 cell development (22), can modulate disease severity in EAE.…”

“…Based on the function of Rai as a negative regulator of Th17 cell development and lupus autoimmunity (22,23), which suggests a potential protective function of Rai in MS pathogenesis, we assessed the impact of Rai deficiency on EAE development. Rai 2/2 mice and their WT counterparts in the C57BL/6 background were immunized with the myelin peptide MOG in the presence of CFA and pentoxifylline and monitored for clinical signs.…”

“…The strength of the TCR signal as well as of individual components of the TCR signaling cascade, including protein kinases (Fyn, Lck, Itk, protein kinase C-u, Akt1, Erk, p38), adaptors (LAT, SIT, raftlin, CARMA-1), and ubiquitin ligases (GRAIL, Itch), has been implicated in the differentiation and function of CD4 + T cells (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). We have recently identified Rai (also known as ShcC), a member of the Shc family of protein adaptors (21), as a negative regulator of Th17 cell development and expansion both in vitro and in vivo (22). Consistent with this finding, genetic ablation of Rai in mice results in the development of lupus-like autoimmunity, characterized by the presence of circulating autoantibodies, splenomegaly associated with spontaneous T and B cell activation, and crescential glomerulonephritis (23).…”