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Opposing regulation of T cell function by Egr-1/NAB2 and Egr-2/Egr-3

Sam Collins1, Michael A Lutz, Paul E Zarek

  • 1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

European Journal of Immunology
|January 19, 2008
PubMed

Insights

The early growth response (Egr) and NGFI-A-binding protein (NAB)2 transcription factors regulate T cell function. Egr-2 and Egr-3 inhibit T cell activation, controlling immune responses and autoimmune disease.

Area of Science:

  • Immunology
  • Molecular Biology
  • Transcription Factor Regulation

Background:

  • T-cell receptor (TCR) signaling activates nuclear factor of activated T-cells (NF-AT), influencing genes related to T cell anergy and activation.
  • Dissecting TCR-induced genetic programs is crucial for understanding T cell function and dysfunction.

Purpose of the Study:

  • To investigate the roles of early growth response (Egr) transcription factors and NGFI-A-binding protein (NAB)2 in regulating T cell activation and inhibition.
  • To elucidate the regulatory pathways and functional consequences of Egr and NAB2 expression in T cells.

Main Methods:

  • Analysis of gene expression patterns in response to TCR stimulation.
  • Investigating the upstream regulatory mechanisms involving NF-AT and AP-1.
  • Utilizing gene knockout (null) and transgenic mouse models to assess T cell function.
  • Employing an in vivo model of autoimmune pneumonitis to evaluate disease pathology.

Main Results:

  • TCR-induced Egr-1 and NAB2 enhance T cell function, while Egr-2 and Egr-3 inhibit it.
  • Egr-2 and Egr-3 are induced by NF-AT independently of AP-1, whereas Egr-1 and NAB2 require AP-1.
  • Egr-3 acts upstream of Egr-2, and both Egr-2/3 mechanistically suppress Egr-1/NAB2 expression.
  • T cells from Egr-2/3 null mice exhibit hyperresponsiveness, while Egr-3 overexpressing cells are hyporesponsive.
  • In vivo, Egr-3 null mice show exacerbated autoimmune pneumonitis, and Egr-3 overexpressing mice show reduced disease.

Conclusions:

  • The Egr/NAB gene network, including Egr-1, -2, -3, and NAB2, plays a critical role in controlling T cell fate during antigen recognition.
  • Egr-2 and Egr-3 act as key inhibitory regulators of T cell activation, impacting immune homeostasis and autoimmune disease development.

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