title: Stepwise epigenetic and phenotypic alterations poise CD8+ T cells to mediate airway hyperresponsiveness and inflammation.
abstract: The functional plasticity of CD8(+) T cells in an atopic environment, encompassing a spectrum from IFN-γ- to IL-13-producing cells, is pivotal in the development of allergic airway hyperresponsiveness and inflammation, and yet remains mechanistically undefined. We demonstrate that CD8(+) T cell IL-13 induction proceeded through a series of distinct IL-4/GATA3-regulated stages characterized by gene expression and epigenetic changes. In vivo, CD8(+) T cells exposed to an environment rich in IL-4 displayed epigenetic changes at the GATA3 and IL-13 promoter indicative of transcriptional activation and IL-13 production. In vitro, IL-4 triggered the stepwise molecular conversion of CD8(+) T cells from IFN-γ to IL-13 production. During the initial stage, IL-4 suppressed T-bet and induced GATA3 expression, characterized by enhanced activating histone modifications and RNA polymerase II (Pol II) recruitment to the GATA3 locus. Notably, recruitment of GATA3 and RNA Pol II to the IL-13 promoter was also detected at this initial stage. However, enhanced IL-13 transcription only occurred at a later stage after TCR stimulation, indicating that IL-4-induced GATA3 recruitment poises the IL-13 locus for TCR-mediated transcription. Thus, both in vivo and in vitro, an atopic (IL-4) environment poises CD8(+) T cells via stepwise epigenetic and phenotypic mechanisms for pathogenic conversion to IL-13 production, which is ultimately triggered via an allergen-mediated TCR stimulus.
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jia
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.forename: Junyan
authors.initials: J
authors.lastname: Han
authors.forename: Anthony
authors.initials: A
authors.lastname: Joetham
authors.forename: Roland A
authors.initials: RA
authors.lastname: Marcus
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lucas
authors.forename: Brian P
authors.initials: BP
authors.lastname: O'Connor
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic / Q000276:immunology*; D016130:Immunophenotyping / Q000379:methods; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*