TY - JOUR
T1 - c-Abl-mediated tyrosine phosphorylation of the T-bet DNA-binding domain regulates CD4 + T-cell differentiation and allergic lung inflammation
AU - Chen, An
AU - Lee, Sang Myeong
AU - Gao, Beixue
AU - Shannon, Stephen
AU - Zhu, Zhou
AU - Fang, Deyu
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=79961146064&partnerID=8YFLogxK
U2 - 10.1128/MCB.05383-11
DO - 10.1128/MCB.05383-11
M3 - Article
C2 - 21690296
AN - SCOPUS:79961146064
SN - 0270-7306
VL - 31
SP - 3445
EP - 3456
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 16
ER -