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J Immunol. 2015 Jul 1;195(1):87-95. doi: 10.4049/jimmunol.1500054. Epub 2015 May 22.

Unexpected Role for Adaptive αβTh17 Cells in Acute Respiratory Distress Syndrome.

Author information

1
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;
2
Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143;
3
Department of Medicine, San Francisco General Hospital, San Francisco, CA 94110;
4
Adaptive Biotechnologies, Seattle, WA 98102;
5
Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121;
6
Department of Pediatrics, UCSF Benioff Children's Hospital Oakland, Oakland, CA 94609;
7
Department of Anesthesia, Cardiovascular Research Institute, San Francisco, CA 94158; Department of Medicine, Cardiovascular Research Institute, San Francisco, CA 94158;
8
University of California, Berkeley, Berkeley, CA 94720; and.
9
Center for Infection and Immunity, Queen's University of Belfast, Belfast BT7 1NN, United Kingdom.
10
Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; dean.sheppard@ucsf.edu.

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.

PMID:
26002979
PMCID:
PMC4475475
DOI:
10.4049/jimmunol.1500054
[Indexed for MEDLINE]
Free PMC Article

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