The Shc family protein adaptor, Rai, acts as a negative regulator of Th17 and Th1 cell development.
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.
University of Siena, Via Aldo Moro, Siena, Italy.
Maria Teresa
MT
Savino
Cristina
C
Ulivieri
Giacomo
G
Emmi
Domenico
D
Prisco
Giulia
G
De Falco
Barbara
B
Ortensi
Enrico
E
Beccastrini
Lorenzo
L
Emmi
Giuliana
G
Pelicci
Mario M
MM
D'Elios
Cosima T
CT
Baldari
D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation; D002465:Cell Movement; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
C431552:RAI1 protein, human; C502844:Rai1 protein, mouse; D011948:Receptors, Antigen, T-Cell; D015534:Trans-Activators; D014157:Transcription Factors