title: IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells.
abstract: Type 2 effector production of IL-13, a demonstrated requirement in models of fibrosis, is routinely ascribed to CD4(+) Th2 cells. We now demonstrate a major role for CD8(+) T cells in a murine model of sterile lung injury. These pulmonary CD8(+) T cells differentiate into IL-13-producing Tc2 cells and play a major role in a bleomycin-induced model of fibrosis. Differentiation of these Tc2 cells in the lung requires IL-21, and bleomycin treated IL-21- and IL-21R-deficient mice develop inflammation but not fibrosis. Moreover, IL-21R-expressing CD8(+) cells are sufficient to reconstitute the fibrotic response in IL-21R-deficient mice. We further show that the combination of IL-4 and IL-21 skews naive CD8(+) T cells to produce IL-21, which, in turn, acts in an autocrine manner to support robust IL-13 production. Our data reveal a novel pathway involved in the onset and regulation of pulmonary fibrosis and identify Tc2 cells as key mediators of fibrogenesis.
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Tia Y
authors.initials: TY
authors.lastname: Brodeur
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
authors.forename: Tara E
authors.initials: TE
authors.lastname: Robidoux
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; and.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Weinstein
authors.affiliation: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Craft
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Susan L
authors.identifier: http://orcid.org/0000-0002-3643-8018
authors.initials: SL
authors.lastname: Swain
authors.affiliation: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; ann.rothstein@umassmed.edu.
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000276:immunology; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: C508118:Il21r protein, mouse; D018793:Interleukin-13; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D001761:Bleomycin; D015847:Interleukin-4; D000098546:Interleukin-21