| First Author | Dodson LF | Year | 2009 |
| Journal | Mol Cell Biol | Volume | 29 |
| Issue | 13 | Pages | 3710-21 |
| PubMed ID | 19398586 | Mgi Jnum | J:149888 |
| Mgi Id | MGI:3849340 | Doi | 10.1128/MCB.01869-08 |
| Citation | Dodson LF, et al. (2009) Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation. Mol Cell Biol 29(13):3710-21 |
| abstractText | Despite extensive study, the role of phosphatidylinositol 3-kinase (PI3-kinase) activation in CD28 function has been highly contentious. To definitively address this question, we generated knock-in mice expressing mutations in two critical domains of the cytoplasmic tail of CD28. Mutation of the proximal tyrosine motif interrupted PI3-kinase binding and prevented CD28-dependent phosphorylation of protein kinase B (PKB)/Akt; however, there was no detectable effect on interleukin-2 (IL-2) secretion, expression of Bcl-X(L), or on T-cell function in vivo. Furthermore, we demonstrate that signaling initiated by the C-terminal proline motif is directly responsible for tyrosine phosphorylation of phosphoinosotide-dependent kinase 1, protein kinase C theta, and glycogen synthase kinase 3beta, as well as contributing to threonine phosphorylation of PKB. T cells mutated in this domain were profoundly impaired in IL-2 secretion, and the mice had marked impairment of humoral responses as well as less severe disease manifestations in experimental allergic encephalomyelitis. These data demonstrate that the distal proline motif initiates a critical nonredundant signaling pathway, whereas direct activation of PI3-kinase by the proximal tyrosine motif of CD28 is not required for normal T-cell function. |
