Signaling through Itk promotes T helper 2 differentiation via negative regulation of T-bet

Immunity. 2004 Jul;21(1):67-80. doi: 10.1016/j.immuni.2004.06.009.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / physiology
  • Cell Differentiation
  • Gene Expression Regulation*
  • Mice
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction*
  • T-Box Domain Proteins
  • Th1 Cells / physiology
  • Th2 Cells / physiology*
  • Transcription Factors / genetics*

Substances

  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • Tec protein-tyrosine kinase
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase