Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet.
The Tec family tyrosine kinase, Itk, is critical for PLC-gamma1 activation downstream of the TCR. Studies of Itk-/- mice have demonstrated a requirement for Itk in Th2 cytokine production and protective immunity to parasitic infections. Here we address the mechanism by which Itk regulates Th2 differentiation. We find that naive Itk-/- CD4+ T cells respond normally to cytokine skewing signals and can differentiate efficiently into either Th1 or Th2 lineage cells. In the absence of skewing cytokines, wild-type CD4+ T cells stimulated with low-avidity ligands preferentially express GATA-3 mRNA and differentiate into Th2 cells. Under these same stimulation conditions, Itk-/- T cells produce large amounts of T-bet mRNA and differentiate into IFN-gamma-producing cells. Furthermore, Itk is upregulated during Th2 differentiation, while Rlk, a related Tec kinase, disappears rapidly from differentiating Th2 cells. Together, these findings provide a molecular explanation for the essential role of Itk in Th2 differentiation.
Miller
Andrew T
AT
Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester 01655, USA.
Wilcox
Heather M
HM
Lai
Zhongbin
Z
Berg
Leslie J
LJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D000098815:T-bet Transcription Factor
D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase