TY - JOUR
T1 - The Shc family protein adaptor, Rai, acts as a negative regulator of Th17 and Th1 cell development
AU - Savino, Maria Teresa
AU - Ulivieri, Cristina
AU - Emmi, Giacomo
AU - Prisco, Domenico
AU - de Falco, Giulia
AU - Ortensi, Barbara
AU - Beccastrini, Enrico
AU - Emmi, Lorenzo
AU - Pelicci, Giuliana
AU - D'Elios, Mario M.
AU - Baldari, Cosima T.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - Cell differentiation
KW - Signal transduction
KW - Systemic lupus erythematosus
KW - T cell receptors
KW - Th2 cells
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UR - http://www.scopus.com/inward/citedby.url?scp=84875684192&partnerID=8YFLogxK
U2 - 10.1189/jlb.0712331
DO - 10.1189/jlb.0712331
M3 - Article
C2 - 23345394
AN - SCOPUS:84875684192
VL - 93
SP - 549
EP - 559
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
SN - 0741-5400
IS - 4
ER -