FEBS Letters
Volume 581, Issue 27 , Pages 5199-5206, 13 November 2007

Contribution of IL-12R mediated feedback loop to Th1 cell differentiation

Edited by Giulio Superti-Furga

  • Attila Becskei

      Affiliations

    • Institute of Molecular Biology, University of Zurich, Winterthurerstrasse, 190, 8057 Zurich, Switzerland
    • Corresponding Author InformationCorresponding author.
  • ,
  • Michael J. Grusby

      Affiliations

    • Department of Immunology and Infectious Diseases, Harvard School of Public Health and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA

Received 20 August 2007; received in revised form 1 October 2007; accepted 5 October 2007. published online 12 October 2007.

Abstract 

T helper 1 (Th1) cell fate is induced by overlapping signaling pathways, whose kinetic principles and regulatory motifs are largely unknown. We identified a simple positive feedback loop in the STAT4 signaling pathway, whereby activation by IL-12 leads to the increased expression in IL-12 receptor. A computational analysis shows that this feedback loop synergizes with the one mediated by the IFN-γ secreted by differentiating cells, when the induction of Th1 cell fate is weak. Positive feedback loops are often utilized to enhance phenotypic differentiation. This effect was confirmed by experiments showing that stochastic fluctuations in the expression of IL-12 receptor gene were amplified, leading to two discrete levels of expression in a cell population.

Abbreviations: Th1, T helper 1

Keywords: Positive feedback, Stochastic, Interleukin-27, T-bet, Computational modeling

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PII: S0014-5793(07)01064-2

doi:10.1016/j.febslet.2007.10.007

FEBS Letters
Volume 581, Issue 27 , Pages 5199-5206, 13 November 2007