Elevated and Sustained Expression of the Transcription Factors Egr1 and Egr2 Controls NKT Lineage Differentiation in Response to TCR Signaling

Nat Immunol. 2012 Feb 5;13(3):264-71. doi: 10.1038/ni.2230.

Abstract

Interactions driven by the T cell antigen receptor (TCR) determine the lineage fate of CD4(+)CD8(+) thymocytes, but the molecular mechanisms that induce the lineage-determining transcription factors are unknown. Here we found that TCR-induced transcription factors Egr2 and Egr1 had higher and more-prolonged expression in precursors of the natural killer T (NKT) than in cells of conventional lineages. Chromatin immunoprecipitation followed by deep sequencing showed that Egr2 directly bound and activated the promoter of Zbtb16, which encodes the NKT lineage-specific transcription factor PLZF. Egr2 also bound the promoter of Il2rb, which encodes the interleukin 2 (IL-2) receptor β-chain, and controlled the responsiveness to IL-15, which signals the terminal differentiation of the NKT lineage. Thus, we propose that persistent higher expression of Egr2 specifies the early and late stages of NKT lineage differentiation, providing a discriminating mechanism that enables TCR signaling to 'instruct' a thymic lineage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Lineage*
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / immunology*
  • Early Growth Response Protein 1 / metabolism
  • Early Growth Response Protein 2 / genetics
  • Early Growth Response Protein 2 / immunology*
  • Early Growth Response Protein 2 / metabolism
  • Humans
  • Kruppel-Like Transcription Factors / immunology
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Natural Killer T-Cells / cytology
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Promoter Regions, Genetic
  • Promyelocytic Leukemia Zinc Finger Protein
  • Protein Binding
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction*

Substances

  • Early Growth Response Protein 1
  • Early Growth Response Protein 2
  • Egr1 protein, mouse
  • Egr2 protein, mouse
  • Kruppel-Like Transcription Factors
  • Promyelocytic Leukemia Zinc Finger Protein
  • Receptors, Antigen, T-Cell
  • Zbtb16 protein, mouse

Associated data

  • GEO/GSE34254