Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12

Immunity. 2009 May;30(5):673-83. doi: 10.1016/j.immuni.2009.03.013. Epub 2009 Apr 30.


Differentiation of naive T lymphocytes into type I T helper (Th1) cells requires interferon-gamma and interleukin-12. It is puzzling that interferon-gamma induces the Th1 transcription factor T-bet, whereas interleukin-12 mediates Th1 cell lineage differentiation. We use mathematical modeling to analyze the expression kinetics of T-bet, interferon-gamma, and the IL-12 receptor beta2 chain (IL-12Rbeta2) during Th1 cell differentiation, in the presence or absence of interleukin-12 or interferon-gamma signaling. We show that interferon-gamma induced initial T-bet expression, whereas IL-12Rbeta2 was repressed by T cell receptor (TCR) signaling. The termination of TCR signaling permitted upregulation of IL-12Rbeta2 by T-bet and interleukin-12 signaling that maintained T-bet expression. This late expression of T-bet, accompanied by the upregulation of the transcription factors Runx3 and Hlx, was required to imprint the Th cell for interferon-gamma re-expression. Thus initial polarization and subsequent imprinting of Th1 cells are mediated by interlinked, sequentially acting positive feedback loops of TCR-interferon-gamma-Stat1-T-bet and interleukin-12-Stat4-T-bet signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Polarity / genetics*
  • Cell Polarity / immunology
  • Core Binding Factor Alpha 3 Subunit / metabolism
  • Genomic Imprinting*
  • Homeodomain Proteins / immunology
  • Homeodomain Proteins / metabolism*
  • Interferon-gamma / genetics*
  • Interleukin-12 / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Receptors, Interleukin-12 / immunology
  • Receptors, Interleukin-12 / metabolism
  • Signal Transduction
  • T-Box Domain Proteins / metabolism
  • Th1 Cells / immunology*
  • Transcription Factors / immunology
  • Transcription Factors / metabolism*


  • Core Binding Factor Alpha 3 Subunit
  • Hlx protein, mouse
  • Homeodomain Proteins
  • Receptors, Interleukin-12
  • Runx3 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • Interleukin-12
  • Interferon-gamma