title: Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGF-β.
abstract: IL-4 plays an important role in the induction of Th2 and Th9 cells, as well as in the inhibition of Th1 cell generation. We show that a combination of IL-4 and TGF-β augments the development of Th1 cells that express CD103 (CD103(+) Th1 cells) if IFN-γ is present. The T-box-containing transcription factor eomesodermin (Eomes) is preferentially expressed in CD103(+) Th1 cells and is involved in IFN-γ production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFN-γ gene loci. TGF-β is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6-signaling pathway. IFN-γ-producing CD103(+) Th1 cells are detected in the intraepithelial lymphocytes of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. To our knowledge, these results represent the first molecular mechanism of IL-4/TGF-β-dependent augmentation of Th1 cell generation and raise the possibility that IL-4 and TGF-β simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions.
authors.affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Tofukuji
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuwahara
authors.forename: Junpei
authors.initials: J
authors.lastname: Suzuki
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yamashita
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008211:Lymphocyte Cooperation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; C491198:Eomes protein, mouse; D020825:T-Box Domain Proteins; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma