An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+ T cells.
IL-27 is a novel IL-12 family member that plays a role in the early regulation of Th1 initiation, induces proliferation of naive CD4+ T cells, and synergizes with IL-12 in IFN-gamma production. It has been recently reported that IL-27 induces T-bet and IL-12Rbeta2 expression through JAK1/STAT1 activation. In the present study, we further investigated the JAK/STAT signaling molecules activated by IL-27 and also the role of STAT1 in IL-27-mediated responses using STAT1-deficient mice. In addition to JAK1 and STAT1, IL-27-activated JAK2, tyrosine kinase-2, and STAT2, -3, and -5 in naive CD4+ T cells. The activation of STAT2 and STAT5, but not of STAT3, was greatly diminished in STAT1-deficient naive CD4+ T cells. Comparable proliferative response to IL-27 was observed between STAT1-deficient and wild-type naive CD4+ T cells. In contrast, IL-27 hardly induced T-bet and subsequent IL-12Rbeta2 expression, and synergistic IFN-gamma production by IL-27 and IL-12 was impaired in STAT1-deficient naive CD4+ T cells. Moreover, IL-27 augmented the expression of MHC class I on naive CD4+ T cells in a STAT1-dependent manner. These results suggest that IL-27 activates JAK1 and -2, tyrosine kinase-2, STAT1, -2, -3, and -5 in naive CD4+ T cells and that STAT1 plays an indispensable role in IL-27-induced T-bet and subsequent IL-12Rbeta2 expression and MHC class I expression as well but not proliferation, while STAT3 presumably plays an important role in IL-27-induced proliferation.
Kamiya
Sadahiro
S
Intractable Immune System Disease Research Center, Tokyo Medical University, Japan.
Owaki
Toshiyuki
T
Morishima
Noriko
N
Fukai
Fumio
F
Mizuguchi
Junichiro
J
Yoshimoto
Takayuki
T
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D007399:Interphase / Q000235:genetics / Q000276:immunology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020825:T-Box Domain Proteins; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000098815:T-bet Transcription Factor
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; C486767:Il27 protein, mouse; D007378:Interleukins; C464565:MYDGF protein, human; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C494087:Stat3 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse