title: Th22 Cells Form a Distinct Th Lineage from Th17 Cells In Vitro with Unique Transcriptional Properties and Tbet-Dependent Th1 Plasticity.
abstract: Th22 cells are a major source of IL-22 and have been found at sites of infection and in a range of inflammatory diseases. However, their molecular characteristics and functional roles remain largely unknown because of our inability to generate and isolate pure populations. We developed a novel Th22 differentiation assay and generated dual IL-22/IL-17A reporter mice to isolate and compare pure populations of cultured Th22 and Th17 cells. Il17a fate-mapping and transcriptional profiling provide evidence that these Th22 cells have never expressed IL-17A, suggesting that they are potentially a distinct cell lineage from Th17 cells under in vitro culture conditions. Interestingly, Th22 cells also expressed granzymes, IL-13, and increased levels of Tbet. Using transcription factor-deficient cells, we demonstrate that RORγt and Tbet act as positive and negative regulators of Th22 differentiation, respectively. Furthermore, under Th1 culture conditions in vitro, as well as in an IFN-γ-rich inflammatory environment in vivo, Th22 cells displayed marked plasticity toward IFN-γ production. Th22 cells also displayed plasticity under Th2 conditions in vitro by upregulating IL-13 expression. Our work has identified conditions to generate and characterize Th22 cells in vitro. Further, it provides evidence that Th22 cells develop independently of the Th17 lineage, while demonstrating plasticity toward both Th1- and Th2-type cells.
authors.affiliation: Priority Research Centre for Healthy Lungs, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors.forename: Maximilian W
authors.initials: MW
authors.lastname: Plank
authors.affiliation: Priority Research Centre for Healthy Lungs, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors.forename: Gerard E
authors.initials: GE
authors.lastname: Kaiko
authors.affiliation: Priority Research Centre for Healthy Lungs, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors.forename: Steven
authors.identifier: 0000-0003-1240-5964
authors.initials: S
authors.lastname: Maltby
authors.affiliation: Priority Research Centre for Healthy Lungs, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Weaver
authors.affiliation: Priority Research Centre for Healthy Lungs, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors.forename: Hock L
authors.initials: HL
authors.lastname: Tay
authors.affiliation: Laboratory of Immunoregulation, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.affiliation: Division of Molecular Immunology, The Francis Crick Institute, London NW1 1AT, United Kingdom.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Wilson
authors.affiliation: Laboratory of Immunoregulation, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702; and.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Durum
authors.affiliation: Priority Research Centre for Healthy Lungs, Department of Microbiology and Immunology, School of Pharmacy and Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2308, Australia; paul.foster@newcastle.edu.au.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D000066670:Cell Plasticity; D002478:Cells, Cultured; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097043:Interleukin-22; D000098815:T-bet Transcription Factor
chemical_list: D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020825:T-Box Domain Proteins; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; D000098815:T-bet Transcription Factor