IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms.
IL-27, a novel heterodimeric cytokine produced by antigen-presenting cells, signals through the T cell cytokine receptor (TCCR)/WSX-1 expressed on naïve CD4+ T cells and natural killer cells. TCCR/WSX-1 deficiency results in delayed T helper type 1 (TH1) development through an unresolved mechanism. We report here that IL-27 stimulation in developing murine T helper cells potently induces the expression of the major TH1-specific transcription factor T-bet and its downstream target IL-12R beta2, independently of IFN gamma. In addition, IL-27 suppresses basal expression of GATA-3, the critical TH2-specific transcription factor that inhibits TH1 development by down-regulating signal transducer and activator of transcription (Stat) 4. IL-27 signaling through TCCR/WSX-1 induces phosphorylation of Stat1, Stat3, Stat4, and Stat5. Stat1 is required for suppression of GATA-3, but T-bet induction by IL-27 can also be mediated through a Stat1-independent pathway. Despite its TH1-like signaling profile, IL-27 is not sufficient to drive the differentiation of CD4+ T cells into IFN gamma-producing cells. Similarly, IL-27 induces T-bet expression in primary natural killer cells, but this does not result in an increase of IFN gamma production or cytotoxic activity. Therefore, although IL-27 is unable to drive IFN gamma production on its own, it plays an important role in the early steps of TH1 commitment by contributing in a paracrine manner to the control of IL-12 responsiveness.
Lucas
Sophie
S
Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Ghilardi
Nico
N
Li
Ji
J
de Sauvage
Frédéric J
FJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D002455:Cell Division; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D050990:GATA3 Transcription Factor; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism / Q000502:physiology*; D007694:Killer Cells, Natural / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C494748:Gata3 protein, mouse; C486767:Il27 protein, mouse; D007378:Interleukins; C464565:MYDGF protein, human; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma