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CUTTING EDGE |
* Department of Medicine and
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Recent studies suggest that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays a critical role in the maintenance of self-tolerance. Using T cell-specific PTEN knockout mice (PTEN
T), we have identified a novel mechanism by which PTEN regulates T cell tolerance. We found that TCR stimulation alone, without CD28 costimulation, is sufficient to induce hyperactivation of the PI3K pathway, which leads to enhanced IL-2 production by naive PTENT T cells. Importantly, as a result of this increased response to TCR stimulation, PTENT CD4+ T cells no longer require CD28 costimulation for in vitro or in vivo expansion. In fact, unlike wild-type T cells, PTENT CD4+ T cells are not anergized by delivery of TCR stimulation alone. These data suggest that by negatively regulating TCR signals, PTEN imposes a requirement for CD28 costimulation, thus defining a novel mechanism for its role in self-tolerance.
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 National Institutes of Health Grant AI-43620 (to Y.C. and L.A.T.) and by a grant from the Cancer Research Institute (to J.L.B.).
2 Address correspondence and reprint requests to Dr. Laurence A. Turka, University of Pennsylvania, 700 CRB, 415 Curie Boulevard, Philadelphia, PA 19104-6144. E-mail address: turka{at}mail.med.upenn.edu
3 Abbreviations used in this paper: PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; WT, wild type; p, phosphorylated; SEB, staphylococcal enterotoxin B.
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