title: Unexpected Role for Adaptive αβTh17 Cells in Acute Respiratory Distress Syndrome.
abstract: Acute respiratory distress syndrome (ARDS) is a devastating disorder characterized by increased alveolar permeability with no effective treatment beyond supportive care. Current mechanisms underlying ARDS focus on alveolar endothelial and epithelial injury caused by products of innate immune cells and platelets. However, the role of adaptive immune cells in ARDS remains largely unknown. In this study, we report that expansion of Ag-specific αβTh17 cells contributes to ARDS by local secretion of IL-17A, which in turn directly increases alveolar epithelial permeability. Mice with a highly restrictive defect in Ag-specific αβTh17 cells were protected from experimental ARDS induced by a single dose of endotracheal LPS. Loss of IL-17 receptor C or Ab blockade of IL-17A was similarly protective, further suggesting that IL-17A released by these cells was responsible for this effect. LPS induced a rapid and specific clonal expansion of αβTh17 cells in the lung, as determined by deep sequencing of the hypervariable CD3RβVJ region of the TCR. Our findings could be relevant to ARDS in humans, because we found significant elevation of IL-17A in bronchoalveolar lavage fluid from patients with ARDS, and rIL-17A directly increased permeability across cultured human alveolar epithelial monolayers. These results reveal a previously unexpected role for adaptive immune responses that increase alveolar permeability in ARDS and suggest that αβTh17 cells and IL-17A could be novel therapeutic targets for this currently untreatable disease.
authors.affiliation: Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94110;
authors.forename: John T
authors.initials: JT
authors.lastname: Li
authors.affiliation: Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143;
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Melton
authors.affiliation: Department of Medicine, San Francisco General Hospital, San Francisco, CA 94110;
authors.forename: George
authors.initials: G
authors.lastname: Su
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102;
authors.forename: David E
authors.initials: DE
authors.lastname: Hamm
authors.affiliation: Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121;
authors.forename: Michael
authors.initials: M
authors.lastname: LaFemina
authors.affiliation: Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA 94609;
authors.forename: James
authors.initials: J
authors.lastname: Howard
authors.affiliation: Department of Anesthesia, Cardiovascular Research Institute, San Francisco, CA 94158; Department of Medicine, Cardiovascular Research Institute, San Francisco, CA 94158;
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Fang
authors.affiliation: University of California, Berkeley, Berkeley, CA 94720; and.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Bhat
authors.affiliation: Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143;
authors.forename: Kieu-My
authors.initials: KM
authors.lastname: Huynh
authors.affiliation: Center for Infection and Immunity, Queen's University of Belfast, Belfast BT7 1NN, United Kingdom.
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: O'Kane
authors.affiliation: Center for Infection and Immunity, Queen's University of Belfast, Belfast BT7 1NN, United Kingdom.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ingram
authors.affiliation: Center for Infection and Immunity, Queen's University of Belfast, Belfast BT7 1NN, United Kingdom.
authors.forename: Roshell R
authors.initials: RR
authors.lastname: Muir
authors.affiliation: Center for Infection and Immunity, Queen's University of Belfast, Belfast BT7 1NN, United Kingdom.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: Department of Anesthesia, Cardiovascular Research Institute, San Francisco, CA 94158; Department of Medicine, Cardiovascular Research Institute, San Francisco, CA 94158;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; dean.sheppard@ucsf.edu.
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010539:Permeability; D061251:Primary Cell Culture; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000276:immunology; D012128:Respiratory Distress Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: D000906:Antibodies; C508717:IL17A protein, human; D020381:Interleukin-17; D008070:Lipopolysaccharides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D053722:Receptors, Interleukin-17