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* Institut National de la Santé et de la Recherche Médicale Unit 576 and
Laboratoire d’Immunologie, Centre Hospitalier de l’Université de Nice, University of Nice-Sophia Antipolis, Nice, France;
Program in Host-Pathogen Interactions, University of California, San Francisco, CA 94158; and
Departments of Biochemistry and Medicine, University of Washington, Seattle, WA 98195
CD47 on the surface of T cells was shown in vitro to mediate either T cell activation or, in the presence of high amounts of thrombospondin (TSP), T cell apoptosis. We report here that CD47-deficient mice, as well as TSP-1 or TSP-2-deficient mice, sustain oxazolone-induced inflammation for more than four days, whereas wild-type mice reduce the inflammation within 48 h. We observe that prolonged inflammation in CD47-, TSP-1-, or TSP-2-deficient mice is accompanied by a local deficiency of T cell apoptosis. Finally, we show that upon activation normal T cells increase the expression of the proapoptotic Bcl-2 family member BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein) and undergo CD47-mediated apoptosis. This finding is consistent with our previous demonstration of a physical interaction between BNIP3 and CD47 that inhibits BNIP3 degradation by the proteasome, sensitizing T cells to CD47-induced apoptosis. Overall, these results reveal an important role in vivo for this new CD47/BNIP3 pathway in limiting inflammation by controlling the number of activated T cells.
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 grants from the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche sur le Cancer, the Fondation pour la Recherche Médicale and the Cancéropôle Provence-Alpes-Côte d’Azur. The generation of TSP-1–/– and TSP-2–/– mice was supported by National Institutes of Health Grant AR 45418 (to P.B.).
2 Address correspondence and reprint requests to Dr. Alain Bernard, Institut National de la Santé et de la Recherche Médicale unit 576, University of Nice-Sophia Antipolis, Hôpital de l’Archet I, 151 rue Saint Antoine de Ginestière, Nice, France. E-mail address: abernard{at}unice.fr
3 Abbreviations used in this paper: SIRP, signal-regulatory protein; 7-AAD, 7-aminoactinomycin D; BNIP3, Bcl-2/adenovirus E1B 19-kDa interacting protein 3; DTH, delayed type hypersensitivity; LN, lymph node; MFI, mean fluorescence intensity; TSP, thrombospondin; WT, wild type.
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