title: Tbet or Continued RORγt Expression Is Not Required for Th17-Associated Immunopathology.
abstract: The discovery of Th17 cell plasticity, in which CD4(+) IL-17-producing Th17 cells give rise to IL-17/IFN-γ double-producing cells and Th1-like IFNγ(+) ex-Th17 lymphocytes, has raised questions regarding which of these cell types contribute to immunopathology during inflammatory diseases. In this study, we show using Helicobacter hepaticus-induced intestinal inflammation that IL-17A(Cre)- or Rag1(Cre)-mediated deletion of Tbx21 has no effect on the generation of IL-17/IFN-γ double-producing cells, but leads to a marked absence of Th1-like IFNγ(+) ex-Th17 cells. Despite the lack of Th1-like ex-Th17 cells, the degree of H. hepaticus-triggered intestinal inflammation in mice in which Tbx21 was excised in IL-17-producing or Rag1-expressing cells is indistinguishable from that observed in control mice. In stark contrast, using experimental autoimmune encephalomyelitis, we show that IL-17A(Cre)-mediated deletion of Tbx21 prevents the conversion of Th17 cells to IL-17A/IFN-γ double-producing cells as well as Th1-like IFN-γ(+) ex-Th17 cells. However, IL-17A(Cre)-mediated deletion of Tbx21 has only limited effects on disease course in this model and is not compensated by Ag-specific Th1 cells. IL-17A(Cre)-mediated deletion of Rorc reveals that RORγt is essential for the maintenance of the Th17 cell lineage, but not immunopathology during experimental autoimmune encephalomyelitis. These results show that neither the single Th17 subset, nor its progeny, is solely responsible for immunopathology or autoimmunity.
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Verena
authors.identifier: 0000-0002-8354-8551
authors.initials: V
authors.lastname: Brucklacher-Waldert
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Cristina
authors.identifier: 0000-0001-6746-932X
authors.initials: C
authors.lastname: Ferreira
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Silvia
authors.initials: S
authors.lastname: Innocentin
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York YO10 5DD, United Kingdom; and.
authors.forename: Shraddha
authors.identifier: 0000-0003-2689-9723
authors.initials: S
authors.lastname: Kamdar
authors.affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: David R
authors.identifier: 0000-0003-3757-7594
authors.initials: DR
authors.lastname: Withers
authors.affiliation: Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York YO10 5DD, United Kingdom; and.
authors.forename: Marika C
authors.identifier: 0000-0003-2081-7029
authors.initials: MC
authors.lastname: Kullberg
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, United Kingdom; marc.veldhoen@babraham.ac.uk.
authors.forename: Marc
authors.identifier: 0000-0002-1478-9562
authors.initials: M
authors.lastname: Veldhoen
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology; D004751:Enteritis / Q000276:immunology*; D044923:Helicobacter hepaticus / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000276:immunology; D007422:Intestines / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539901:Rorc protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma