Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli

Immunity. 2010 Jul 23;33(1):35-47. doi: 10.1016/j.immuni.2010.07.004.

Abstract

Distal cis-regulatory elements play essential roles in the T lineage-specific expression of cytokine genes. We have mapped interactions of three trans-acting factors-NF-kappaB, STAT4, and T-bet-with cis elements in the Ifng locus. We find that RelA is critical for optimal Ifng expression and is differentially recruited to multiple elements contingent upon T cell receptor (TCR) or interleukin-12 (IL-12) plus IL-18 signaling. RelA recruitment to at least four elements is dependent on T-bet-dependent remodeling of the Ifng locus and corecruitment of STAT4. STAT4 and NF-kappaB therefore cooperate at multiple cis elements to enable NF-kappaB-dependent enhancement of Ifng expression. RelA recruitment to distal elements was similar in T helper 1 (Th1) and effector CD8(+) T (Tc1) cells, although T-bet was dispensable in CD8 effectors. These results support a model of Ifng regulation in which distal cis-regulatory elements differentially recruit key transcription factors in a modular fashion to initiate gene transcription induced by distinct activation signals.

Publication types

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

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Differentiation
  • Cells, Cultured
  • Chromatin Assembly and Disassembly / genetics
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Regulatory Elements, Transcriptional / genetics
  • STAT4 Transcription Factor / genetics
  • STAT4 Transcription Factor / metabolism*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Box Domain Proteins / metabolism*
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Th1 Cells / pathology
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / immunology
  • Transcription Factor RelA / metabolism*
  • Transcriptional Activation

Substances

  • Interleukin-18
  • NF-kappa B
  • Receptors, Antigen, T-Cell
  • STAT4 Transcription Factor
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factor RelA
  • Interleukin-12
  • Interferon-gamma