title: Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment.
abstract: T cell helper type 2 (Th2) differentiation is driven by a source of IL-4 receptor (IL-4R) that mobilizes IL-4R signaling pathways and the transcription factor GATA-3. Naïve CD4 cells can secrete IL-4 independently of IL-4R signals, but how this secretion is regulated is not understood. Here we demonstrate that costimulation through the tumor necrosis factor receptor family molecule OX40, in synergy with CD28, is essential for high levels of nuclear factor of activated T cells c1 to accumulate in the nucleus of a recently activated naïve T cell. This action is not dependent on either IL-4R or IL-2R signals and results in OX40 controlling initial naïve T cell IL-4 transcription. OX40 signals subsequently enhance nuclear GATA-3 accumulation through an IL-4R-dependent action, leading to Th2 differentiation. These data show that, in the absence of an exogenous source of IL-4, OX40 provides a critical synergistic and temporal signal with other noncytokine receptors to modulate nuclear factor of activated T cells c1 and to promote optimal Th2 generation.
authors.affiliation: Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
authors.forename: Takanori
authors.initials: T
authors.lastname: So
authors.forename: Jianxun
authors.initials: J
authors.lastname: Song
authors.forename: Katsuji
authors.initials: K
authors.lastname: Sugie
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; C505717:Tnfrsf4 protein, mouse; D015847:Interleukin-4