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* Departments of Immunology,
Medical Biophysics, and
Medicine, University of Toronto, Toronto, Ontario, Canada;
Ontario Cancer Institute/Princess Margaret Hospital, Toronto, Ontario, Canada;
¶ Babraham Institute, Babraham, Cambridge, United Kingdom;
|| Laboratory of Cellular and Molecular Biology National Institute on Aging, National Institutes of Health, Baltimore, MD 00000; and
# St. Michael’s Hospital, Toronto, Ontario, Canada
In concert with the TCR, CD28 promotes T cell survival by regulating the expression of the antiapoptotic protein Bcl-xL. The mechanism by which CD28 mediates the induction of Bcl-xL remains unknown. We show that although signaling through the TCR is sufficient to stimulate transcription of Bcl-xL mRNA, CD28, by activating PI3K and mammalian target of rapamycin, provides a critical signal that regulates the translation of Bcl-xL transcripts. We observe that CD28 induced 4E-binding protein-1 phosphorylation, an inhibitor of the translational machinery, and that CD28 costimulation directly augmented the translation of a Bcl-xL 5'-untranslated region reporter construct. Lastly, costimulation by CD28 shifted the distribution of Bcl-xL mRNA transcripts from the pretranslation complex to the translationally active polyribosomes. These results demonstrate that CD28 relieves the translational inhibition of Bcl-xL in a PI3K/mammalian target of rapamycin-dependent manner.
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