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 Blood, 15 May 2008, Vol. 111, No. 10, pp. 5017-5027.
Prepublished online as a Blood First Edition Paper on March 11, 2008; DOI 10.1182/blood-2007-12-130856.

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IMMUNOBIOLOGY

The proapoptotic and antimitogenic protein p66SHC acts as a negative regulator of lymphocyte activation and autoimmunity

Francesca Finetti1, Michela Pellegrini1, Cristina Ulivieri1, Maria Teresa Savino1, Eugenio Paccagnini1, Chiara Ginanneschi2, Luisa Lanfrancone3, Pier Giuseppe Pelicci3, and Cosima T. Baldari1

1 Department of Evolutionary Biology, University of Siena, Siena; 2 Department of Human Pathology and Oncology, Policlinico Le Scotte, University of Siena, Siena; and 3 Department of Molecular Oncology, European Institute of Oncology, Milan, Italy

The ShcA locus encodes 3 protein isoforms that differ in tissue specificity, subcellular localization, and function. Among these, p66Shc inhibits TCR coupling to the Ras/MAPK pathway and primes T cells to undergo apoptotic death. We have investigated the outcome of p66Shc deficiency on lymphocyte development and homeostasis. We show that p66Shc–/– mice develop an age-related lupus-like autoimmune disease characterized by spontaneous peripheral T- and B-cell activation and proliferation, autoantibody production, and immune complex deposition in kidney and skin, resulting in autoimmune glomerulonephritis and alopecia. p66Shc–/– lymphocytes display enhanced proliferation in response to antigen receptor engagement in vitro and more robust immune responses both to vaccination and to allergen sensitization in vivo. The data identify p66Shc as a negative regulator of lymphocyte activation and show that loss of this protein results in breaking of immunologic tolerance and development of systemic autoimmunity.


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