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Cutting Edge: Distinct Motifs Within CD28 Regulate T Cell Proliferation and Induction of Bcl-XL

2001; American Association of Immunologists; Volume: 166; Issue: 9 Linguagem: Inglês

10.4049/jimmunol.166.9.5331

1550-6606

John S. Burr, Nigel D. L. Savage, Grace E. Messah, Stephanie L. Kimzey, Andréy S. Shaw, Robert H. Arch, Jonathan M. Green,

NF-κB Signaling Pathways

Abstract CD28 provides an important costimulatory signal in T cell activation that regulates multiple cellular processes including proliferation and survival. Several signal transduction pathways are activated by CD28; however, the precise biochemical mechanism by which CD28 regulates T cell function remains controversial. Retroviral gene transfer into primary T cells from TCR-transgenic, CD28-deficient mice was used to determine the specific sequences within CD28 that determine function. Discrete regions of the cytoplasmic domain of CD28 were identified that differentially regulate T cell proliferation and induction of the anti-apoptotic protein Bcl-XL. Mutation of C-terminal proline residues abrogated the proliferative and cytokine regulatory features of CD28 costimulation while preserving Bcl-XL induction. Conversely, mutation of residues important in phosphatidylinositol 3-kinase activation partially inhibited proliferation but prevented induction of Bcl-XL. Thus the ability of CD28 to regulate proliferation and induction of Bcl-XL map to distinct motifs, suggesting independent signaling cascades modulate these biologic effects.