CD28 Regulates the Translation of Bcl-xL via the Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Pathway

Abstract

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.

Prolonged TCR/CD28 Engagement Drives IL-2-Independent T Cell Clonal Expansion through Signaling Mediated by the Mammalian Target of Rapamycin

“…More recent evidence, however, proposed mTOR as a target of CD28-dependent signaling (24,51). Accordingly, we found that the engagement of TCR and CD28 induces the rapid and RAPA-sensitive phosphorylation of p70…”

Intracellular Signals of T Cell Costimulation

“…In particular, one tyrosine (Y170 in mouse CD28, Y173 in human CD28) that is important in PI3K activation permits CD28 to recruit SH2-containing signaling molecules, including PI3K, Grb2, and Gads that control the regulation of bcl-xL (21,74). However, whether or not this regulation was dependent on mammalian target of rapamycin pathway is still controversial (13,75). CD28 also promotes expression of bcl-2, bfl-1 (A1), and myeloid cell leukemia sequence 1 (mcl-1) to regulate T cell survival (76)(77)(78).…”

“…CD28 costimulation leads to a dramatic upregulation of IL-2 expression through enhanced transcription and mRNA stabilization (12). In addition, CD28 costimulation also plays an important role in T cell survival, by inducing the expression of antiapoptotic protein bcl-xL and regulating the metabolic activity of T cells (13). Finally, CD28 plays a crucial role on the generation of Th2 responses (14).…”

Ex Vivo Rapamycin Generates Apoptosis-Resistant Donor Th2 Cells That Persist In Vivo and Prevent Hemopoietic Stem Cell Graft Rejection

“…As such, we hypothesized that an enhanced efficacy of rapamycin-generated T cell therapy may be associated with an increase in T cell survival posttransplant. An ability of rapamycin to confer a T cell survival advantage seems somewhat paradoxical because receptor signaling for the prosurvival cytokines IL-7 (20) and the prosurvival costimulatory signal CD28 (21,22) used in our ex vivo T cell expansion method are dependent in part upon mammalian target of rapamycin (mTOR) function. In contrast, mTOR inhibition can mediate antiapoptotic effects in several experimental models (reviewed in Ref.…”