title: c-Abl-mediated tyrosine phosphorylation of the T-bet DNA-binding domain regulates CD4+ T-cell differentiation and allergic lung inflammation.
abstract: The tyrosine kinase c-Abl is required for full activation of T cells, while its role in T-cell differentiation has not been characterized. We report that c-Abl deficiency skews CD4(+) T cells to type 2 helper T cell (Th2) differentiation, and c-Abl(-/-) mice are more susceptible to allergic lung inflammation. c-Abl interacts with and phosphorylates T-bet, a Th1 lineage transcription factor. c-Abl-mediated phosphorylation enhances the transcriptional activation of T-bet. Interestingly, three tyrosine residues within the T-bet DNA-binding domain are the predominant sites of phosphorylation by c-Abl. Mutation of these tyrosine residues inhibits the promoter DNA-binding activity of T-bet. c-Abl regulates Th cell differentiation in a T-bet-dependent manner because genetic deletion of T-bet in CD4(+) T cells abolishes c-Abl-deficiency-mediated enhancement of Th2 differentiation. Reintroduction of T-bet-null CD4(+) T cells with wild-type T-bet, but not its tyrosine mutant, rescues gamma interferon (IFN-γ) production and inhibits Th2 cytokine production. Therefore, c-Abl catalyzes tyrosine phosphorylation of the DNA-binding domain of T-bet to regulate CD4(+) T cell differentiation.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA. chenan7281@yahoo.com
authors.forename: An
authors.initials: A
authors.lastname: Chen
authors.forename: Sang-Myeong
authors.initials: SM
authors.lastname: Lee
authors.forename: Beixue
authors.initials: B
authors.lastname: Gao
authors.forename: Stephen
authors.initials: S
authors.lastname: Shannon
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000502:physiology; D011014:Pneumonia; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism* / Q000502:physiology; D020825:T-Box Domain Proteins / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl