title: Rai acts as a negative regulator of autoimmunity by inhibiting antigen receptor signaling and lymphocyte activation.
abstract: Rai (ShcC) belongs to the family of Shc adaptor proteins and is expressed in neuronal cells, where it acts as a survival factor activating the PI3K/Akt survival pathway. In vivo, Rai protects the brain from ischemic damage. In this study, we show that Rai is expressed in T and B lymphocytes. Based on the finding that Rai(-/-) mice consistently develop splenomegaly, the role of Rai in lymphocyte homeostasis and proliferation was addressed. Surprisingly, as opposed to neurons, Rai was found to impair lymphocyte survival. Furthermore, Rai deficiency results in a reduction in the frequency of peripheral T cells with a concomitant increase in the frequency of B cells. Rai(-/-) lymphocytes display enhanced proliferative responses to Ag receptor engagement in vitro, which correlates with enhanced signaling by the TCR and BCR, and more robust responses to allergen sensitization in vivo. A high proportion of Rai(-/-) mice develop a lupus-like autoimmune syndrome characterized by splenomegaly, spontaneous peripheral T and B cell activation, autoantibody production, and deposition of immune complexes in the kidney glomeruli, resulting in autoimmune glomerulonephritis. The data identify Rai as a negative regulator of lymphocyte survival and activation and show that loss of this protein results in breaking of immunological tolerance and development of systemic autoimmunity.
authors.affiliation: Department of Evolutionary Biology, University of Siena. Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Savino
authors.forename: Barbara
authors.initials: B
authors.lastname: Ortensi
authors.forename: Micol
authors.initials: M
authors.lastname: Ferro
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.forename: Daniela
authors.initials: D
authors.lastname: Fanigliulo
authors.forename: Eugenio
authors.initials: E
authors.lastname: Paccagnini
authors.forename: Stefano
authors.initials: S
authors.lastname: Lazzi
authors.forename: Daniela
authors.initials: D
authors.lastname: Osti
authors.forename: Giuliana
authors.initials: G
authors.lastname: Pelicci
authors.forename: Cosima T
authors.initials: CT
authors.lastname: Baldari
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors* / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C502844:Rai1 protein, mouse; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D015534:Trans-Activators