The contribution of transcription factor IRF1 to the interferon-gamma-interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells.
Interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) drive T helper type 1 (T(H)1) differentiation, but the mechanisms underlying the regulation of the complicated gene networks involved in this differentiation are not fully understood. Here we show that the IFN-gamma-induced transcription factor IRF1 was essential in T(H)1 differentiation by acting on Il12rb1, the gene encoding the IL-12 receptor beta1 subunit (IL-12Rbeta1). IRF1 directly interacted with and activated the Il12rb1 promoter in CD4+ T cells. Notably, the IRF1-dependent induction of IL-12Rbeta1 was essential for IFN-gamma-IL-12 signaling but was dispensable for IL-23-IL-17 signaling. Because both IL-12 and IL-23 bind to and transmit signals through IL-12Rbeta1, our data suggest that distinct thresholds of IL-12Rbeta1 expression are required for T(H)1 versus T(H)-17 differentiation.
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Shin-ichi
S
Kano
Kojiro
K
Sato
Yasuyuki
Y
Morishita
Sabine
S
Vollstedt
Sunhwa
S
Kim
Keith
K
Bishop
Kenya
K
Honda
Masato
M
Kubo
Tadatsugu
T
Taniguchi
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000502:physiology*; D020381:Interleukin-17 / Q000502:physiology; D053759:Interleukin-23 / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D053707:Receptors, Interleukin-12 / Q000502:physiology; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*
C508440:Il12rb1 protein, mouse; D050856:Interferon Regulatory Factor-1; D020381:Interleukin-17; D053759:Interleukin-23; C494258:Irf1 protein, mouse; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D007371:Interferon-gamma