Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled through different signaling pathways.
Despite the clear functional importance of CD28 costimulation, the signaling pathways transduced through CD28 have remained controversial. PI3K was identified early as a candidate for CD28 signaling, but conflicting data during the past decade has left the role of PI3K unresolved. In this report, we have resolved this controversy. We show that mutation of the PI3K interaction site in the cytosolic tail of CD28 site disrupts the ability of CD28 to recruit protein kinase C-theta; to the central supramolecular activation cluster (c-SMAC) region of the immunological synapse, promote NF-kappaB nuclear translocation, and enhance IL-2 gene transcription. In contrast, mutation of the PI3K interaction site had no effect on the ability of CD28 to enhance IL-2 mRNA stability. These results suggest that two distinct pathways mediate CD28-induced up-regulation of IL-2 expression, a PI3K-dependent pathway that may function through the immunological synapse to enhance IL-2 transcription and a PI3K-independent pathway that induces IL-2 mRNA stability.
Sanchez-Lockhart
Mariano
M
David H. Smith Center for Vaccine Biology and Immunology, Aab Institute, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.
Marin
Elides
E
Graf
Beth
B
Abe
Ryo
R
Harada
Yohsuke
Y
Sedwick
Caitlin E
CE
Miller
Jim
J
D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D007376:Interleukin-2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D012323:RNA Processing, Post-Transcriptional / Q000276:immunology*; D020871:RNA Stability / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology*
D018106:CD28 Antigens; D007376:Interleukin-2; D007527:Isoenzymes; D016328:NF-kappa B; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta