| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Evolutionary Biology, University of Siena,
Department of Experimental Oncology, European Institute of Oncology, Milan, and
Department of Clinical Medicine and Immunological Sciences and
Department of Human Pathology and Oncology, Siena, Italy
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Associazione Italiana per la Ricerca sul Cancro. The financial support of Istituto Toscano Tumori and Ministero dell’ Istruzione, dell’ Università e della Ricerca (Progetti di Ricerca di Interesse Nazionale) is also acknowledged.
2 Address correspondence and reprint requests to Dr. Cosima T. Baldari, Department of Evolutionary Biology, University of Siena, Via Aldo Moro 2, 53100 Siena or Dr. Giuliana Pelicci, Department of Molecular Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. E-mail addresses: baldari{at}unisi.it and giuliana.pelicci{at}ifom-ieo-campus.it
3 Abbreviations used in this paper: TNCB, 2,4,6-trinitrochlorobenzene; DTH, delayed-type hypersensivity reaction.
Related articles in The JI:
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
