Rai acts as a negative regulator of autoimmunity by inhibiting antigen receptor signaling and lymphocyte activation

Maria Teresa Savino, Barbara Ortensi, Micol Ferro, Cristina Ulivieri, Daniela Fanigliulo, Eugenio Paccagnini, Stefano Lazzi, Daniela Osti, Giuliana Pelicci, Cosima T. Baldari

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)301-308
Number of pages8
JournalJournal of Immunology
Volume182
Issue number1
Publication statusPublished - Jan 1 2009

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Antigen Receptors
Lymphocyte Activation
Autoimmunity
B-Lymphocytes
Splenomegaly
Lymphocytes
T-Lymphocytes
Shc Signaling Adaptor Proteins
Kidney Glomerulus
Glomerulonephritis
Antigen-Antibody Complex
Phosphatidylinositol 3-Kinases
Autoantibodies
Allergens
Homeostasis
Neurons
Brain
Proteins

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Savino, M. T., Ortensi, B., Ferro, M., Ulivieri, C., Fanigliulo, D., Paccagnini, E., ... Baldari, C. T. (2009). Rai acts as a negative regulator of autoimmunity by inhibiting antigen receptor signaling and lymphocyte activation. Journal of Immunology, 182(1), 301-308.

Rai acts as a negative regulator of autoimmunity by inhibiting antigen receptor signaling and lymphocyte activation. / Savino, Maria Teresa; Ortensi, Barbara; Ferro, Micol; Ulivieri, Cristina; Fanigliulo, Daniela; Paccagnini, Eugenio; Lazzi, Stefano; Osti, Daniela; Pelicci, Giuliana; Baldari, Cosima T.

In: Journal of Immunology, Vol. 182, No. 1, 01.01.2009, p. 301-308.

Research output: Contribution to journalArticle

Savino, MT, Ortensi, B, Ferro, M, Ulivieri, C, Fanigliulo, D, Paccagnini, E, Lazzi, S, Osti, D, Pelicci, G & Baldari, CT 2009, 'Rai acts as a negative regulator of autoimmunity by inhibiting antigen receptor signaling and lymphocyte activation', Journal of Immunology, vol. 182, no. 1, pp. 301-308.
Savino, Maria Teresa ; Ortensi, Barbara ; Ferro, Micol ; Ulivieri, Cristina ; Fanigliulo, Daniela ; Paccagnini, Eugenio ; Lazzi, Stefano ; Osti, Daniela ; Pelicci, Giuliana ; Baldari, Cosima T. / Rai acts as a negative regulator of autoimmunity by inhibiting antigen receptor signaling and lymphocyte activation. In: Journal of Immunology. 2009 ; Vol. 182, No. 1. pp. 301-308.
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