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, c-Rel, and Protein Kinase B1
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* Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada;
Department of Immunology, University of Toronto, Toronto, Ontario, Canada;
Institute for Breast Cancer Research, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada;
Abramson Family Cancer Research Institute, Philadelphia, PA 19104; and
¶ Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
An effective immune response requires the expansion and survival of a large number of activated T cells. This study compared the role of protein kinase C (PKC)
and associated signaling molecules in the survival of activated primary CD4+ vs CD8+ murine T cells. We demonstrate that the absence of PKC resulted in a moderate survival defect in CD4+ T cells and a striking survival defect of CD8+ T lymphocytes. CD8+ T cells lacking the c-Rel, but not the NF-
B1/p50, member of the NF-B family of transcription factors displayed a similar impairment in cell survival as PKC–/– CD8+ T lymphocytes. This implicates c-Rel as a key target of PKC-mediated survival signals in CD8+ T cells. In addition, both c-Rel–/– and PKC–/– T cells also displayed impaired expression of the antiapoptotic Bcl-xL protein upon activation. Changes in Bcl-xL expression, however, did not correlate with the survival of CD4+ or CD8+ lymphocytes. The addition of protein kinase B-mediated survival signals could restore partially CD4+ T cell viability, but did not dramatically influence CD8+ survival. Active protein kinase B was also unable to restore proliferative responses in CD8+ PKC–/– T cells. The survival of CD4+ and CD8+ T cells deficient in either PKC or c-Rel, however, was promoted by the addition of IL-2. Collectively, these data demonstrate that CD4+ and CD8+ T cell survival signals are differentially programmed.
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 the Canadian Institutes for Health Research and National Cancer Institute of Canada, with funds from the Canadian Cancer Society. S.D.S. is supported by a Canadian Institutes for Health Research MD/PhD award. P.S.O. holds a Canada Research Chair.
2 Address correspondence and reprint requests to Dr. Pamela S. Ohashi, The Campbell Institute for Breast Cancer Research, University of Toronto, 610 University Avenue, Room 706, Toronto, Ontario, Canada M5G 2C1. E-mail address: pohashi{at}uhnres.utoronto.ca
3 Abbreviations used in this paper: PKB, protein kinase B; 7AAD, 7-aminoactinomycin D; IKK, IB kinase; MFI, mean fluorescence intensity; PKC, protein kinase C.
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