Cutting edge: Distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-X-L

CD28 provides an important costimulatory signal in T cell activation that r egulates multiple cellular processes including proliferation and survival. Several signal transduction pathways are activated by CD28; however, the pr ecise biochemical mechanism by which CD28 regulates T cell function remains controversial. Retroviral gene transfer into primary T cells from TCR-tran sgenic, CD28-deficient mice was used to determine the specific sequences wi thin CD28 that determine function. Discrete regions of the cytoplasmic doma in of CD28 were identified that differentially regulate T cell proliferatio n and induction of the anti-apoptotic protein Bcl-X-L, Mutation of C-termin al proline residues abrogated the proliferative and cytokine regulatory fea tures of CD28 costimulation while preserving Bcl-X-L induction. Conversely, mutation of residues important in phosphatidylinositol 3-kinase activation partially inhibited proliferation but prevented induction of Bcl-X-L. Thus the ability of CD28 to regulate proliferation and induction of Bcl-X-L map to distinct motifs, suggesting independent signaling cascades modulate the se biologic effects.