Contribution of IL-12R mediated feedback loop to Th1 cell differentiation.
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-gamma 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.
Becskei
Attila
A
Institute of Molecular Biology, University of Zurich, Winterthurerstrasse, 190, 8057 Zurich, Switzerland. attila.becskei@molbio.uzh.ch
Grusby
Michael J
MJ
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D005246:Feedback; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D018664:Interleukin-12; D007378:Interleukins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D000096743:Interferon gamma Receptor; C508443:Il12rb2 protein, mouse; C486767:Il27 protein, mouse; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse