Signal transduction pathways through the T cell costimulatory receptor CD28.
Published: 2004
Language: eng
Number of pages: 157
Description: Upon interaction with its ligands, the B7-1 and B7-2, CD28 becomes tyrosine phosphorylated. Phosphorylation of Y170 of CD28 results in the recruitment of SH2-domain containing proteins, including PI3K, Grb2 and Gads. Using transgenic mice that express a tyrosine to phenylalanine mutant form of CD28 (Y170F) that uncouples these SH2-mediated interactions from CD28, I have shown that the Y170F mutant was unable to upregulate Bcl-XL protein expression, rendering the T cells more susceptible to radiation-induced cell death. Nonetheless, the Y170F mutant prevented the induction of anergy, promoted T cell proliferation, IL-2 secretion and B cell help. These results demonstrate that a single point mutation, Y170F, uncouples CD28 signals required for proliferation or survival.CD28 is a critical costimulatory receptor involved in T cell activation. In concert with the TCR, CD28 promotes survival of T cells by regulating the expression of the anti-apoptotic protein Bcl-XL. This thesis addresses two major aspects of CD28 costimulatory signals. First, the tyrosine residue Y170, within the CD28 cytoplasmic domain is required for CD28 upregulation of Bcl-XL. Second, CD28 regulates Bcl-XL protein translation in a PI3K/mTOR dependent manner.I have further investigated the mechanism by which CD28 mediates the induction of Bcl-XL protein expression. While the TCR signaling was sufficient to stimulate the transcription of Bcl-XL mRNA, CD28 provided a critical signal that regulated Bcl-XL mRNA at the translational level through the activation PI3K and mTOR. I have also shown that phosphorylation of 4E-BP1, an inhibitor of translational machinery, was deficient in CD28 -/- T cells. Furthermore, CD28 costimulation markedly augmented the translation of a Bcl-XL 5'UTR reporter construct. These results demonstrate that CD28 relieves the translational inhibition of Bcl-XL in a PI3K/mTOR dependent manner.
Notes: Adviser:  Robert Rottapel.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2335.