Lck mediates Th2 differentiation through effects on T-bet and GATA-3

J Immunol. 2010 Apr 15;184(8):4178-84. doi: 10.4049/jimmunol.0901282. Epub 2010 Mar 17.

Abstract

The Src family kinase Lck has been shown to be crucial in T cell signaling and development. However, its role in Th effector functions is not well understood. Lck has previously been shown to play a role in the cytokine expression of Th2 cells, but the mechanism by which Lck influences Th2 effector functions is unknown. Using a mouse model, we report that Lck is important in regulating the expression of IL-4 in Th2 skewed cells but is not as necessary for the expression of Th2 cytokines IL-5, IL-10, and IL-13. Furthermore, in the absence of Lck, T-bet and GATA-3 expression is aberrant. Moreover, this atypical expression pattern of T-bet and GATA-3 correlates with increased histone 3 acetylation at the Ifng locus and production of the Th1 cytokine IFN-gamma. We find overexpression of GATA-3 restores IL-4 expression in lck(-/-) Th2 cells; this indicates that the decreased IL-4 expression is due in part to reduced amounts of GATA-3. Taken together, these data imply that Lck mediates Th2 differentiation through effects on T-bet and GATA-3.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • GATA3 Transcription Factor / antagonists & inhibitors*
  • GATA3 Transcription Factor / biosynthesis
  • GATA3 Transcription Factor / genetics
  • Gene Expression Regulation / immunology*
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-4 / antagonists & inhibitors
  • Interleukin-4 / biosynthesis
  • Interleukin-4 / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / deficiency
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • T-Box Domain Proteins / antagonists & inhibitors*
  • T-Box Domain Proteins / biosynthesis
  • T-Box Domain Proteins / genetics
  • Th2 Cells / enzymology*
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism

Substances

  • GATA3 Transcription Factor
  • GATA3 protein, human
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interleukin-4
  • Interferon-gamma
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)