Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12.
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.
Schulz
Edda G
EG
Theoretical Biophysics, Institute of Biology, Humboldt Universität, Invalidenstrasse 42, 10115 Berlin, Germany.
Mariani
Luca
L
Radbruch
Andreas
A
Höfer
Thomas
T
D000818:Animals; D002454:Cell Differentiation; D016764:Cell Polarity / Q000235:genetics* / Q000276:immunology; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism; D018392:Genomic Imprinting; D018398:Homeodomain Proteins / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics*; D018664:Interleukin-12 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D053707:Receptors, Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D000098815:T-bet Transcription Factor
D050677:Core Binding Factor Alpha 3 Subunit; C489999:Hlx protein, mouse; D018398:Homeodomain Proteins; D053707:Receptors, Interleukin-12; C493730:Runx3 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma