Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation

Lindzy F. Dodson, Jonathan S. Boomer, Christine M. Deppong, Dulari D. Shah, Julia Sim, Traci L. Bricker, John H. Russell, Jonathan M. Green

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51 Scopus citations

Abstract

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-XL, 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 Cβ, and glycogen synthase kinase 3β, 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.

Original languageEnglish
Pages (from-to)3710-3721
Number of pages12
JournalMolecular and cellular biology
Volume29
Issue number13
DOIs
StatePublished - Jul 1 2009

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    Dodson, L. F., Boomer, J. S., Deppong, C. M., Shah, D. D., Sim, J., Bricker, T. L., Russell, J. H., & Green, J. M. (2009). Targeted knock-in mice expressing mutations of CD28 reveal an essential pathway for costimulation. Molecular and cellular biology, 29(13), 3710-3721. https://doi.org/10.1128/MCB.01869-08