Mutation of Tec family kinases alters T helper cell differentiation

Nat Immunol. 2001 Dec;2(12):1183-8. doi: 10.1038/ni734.

Abstract

The Tec kinases Rlk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-gamma and mitogen-activated protein kinase. We show here that the mutation of Rlk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type 1 (TH1) and TH2 cytokines. Consistent with these biochemical defects, Itk-/- mice did not generate effective TH2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk-/-Itk-/- mice were able to mount a TH2 response and produced TH2 cytokines in response to this challenge. In addition, Rlk-/-Itk-/- cells showed impaired TCR-induced repression of the TH2-inducing transcription factor GATA-3, suggesting a potential mechanism for TH2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytokines / pharmacology
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • GATA3 Transcription Factor
  • Immunoglobulin E / biosynthesis
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Mutation
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / physiology*
  • RNA, Messenger / biosynthesis
  • Receptors, Antigen, T-Cell / physiology
  • Schistosomiasis mansoni / immunology
  • Schistosomiasis mansoni / pathology
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / enzymology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Th2 Cells / enzymology
  • Th2 Cells / immunology
  • Trans-Activators / biosynthesis
  • Trans-Activators / genetics
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism

Substances

  • Cytokines
  • DNA-Binding Proteins
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • NFATC Transcription Factors
  • Nuclear Proteins
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • Trans-Activators
  • Transcription Factor AP-1
  • Transcription Factors
  • Immunoglobulin E
  • Tec protein-tyrosine kinase
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase