Developmental commitment to the Th2 lineage by extinction of IL-12 signaling.
Developmental-commitment to Th1 or Th2 responses critically influences host susceptibility to particular pathogens. We describe a novel mechanism governing stable commitment to Th2 differentiation. Naive T cells develop strongly polarized Th1 and Th2 profiles by 7 days after activation. However, commitment of these developing cells differs substantially. Although IL-4 reverses early Th1 differentiation, IL-12 cannot reverse early Th2 differentiation. Th1 reversibility results from maintenance of IL-4 signal transduction, whereas Th2 commitment results from rapid loss of IL-12 signaling. The IL-12 signaling defect in Th2 cells results in failure to phosphorylate Jak2, Stat3, and Stat4. Since Th2 cells express the mRNA for the cloned murine IL-12 receptor beta subunit, the signaling defect may involve expression or function of unidentified receptor components. The rapid extinction of IL-12 signaling in Th2 cells provides a demonstration of a mechanism for the stable commitment to a T helper phenotype.
Szabo
S J
SJ
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Jacobson
N G
NG
Dighe
A S
AS
Gubler
U
U
Murphy
K M
KM
D000818:Animals; D001483:Base Sequence; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology; D053614:Janus Kinase 2; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D015398:Signal Transduction / Q000276:immunology*; D053634:TYK2 Kinase; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000502:physiology
D011506:Proteins; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D015534:Trans-Activators; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse