Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch.
CD4(+) T helper cells differentiate into T helper 1 (Th1) or Th2 effector lineages, which orchestrate immunity to different types of microbes. Both Th1 and Th2 differentiation can be induced by Notch, but what dictates which of these programs is activated in response to Notch is not known. By using T cell-specific gene ablation of the Notch effector RBP-J or the Notch1 and 2 receptors, we showed here that Notch was required on CD4(+) T cells for physiological Th2 responses to parasite antigens. GATA-3 was necessary for Notch-induced Th2 differentiation, and we identified an upstream Gata3 promoter as a direct target for Notch signaling. Moreover, absence of GATA-3 turned Notch from a Th2 inducer into a powerful inducer of Th1 differentiation. Therefore, Gata3 is a critical element determining inductive Th2 differentiation and limiting Th1 differentiation by Notch.
Amsen
Derk
D
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. d.amsen@amc.uva.nl
Antov
Andrey
A
Jankovic
Dragana
D
Sher
Alan
A
Radtke
Freddy
F
Souabni
Abdallah
A
Busslinger
Meinrad
M
McCright
Brent
B
Gridley
Thomas
T
Flavell
Richard A
RA
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D051880:Receptors, Notch