Unexpected Role for Adaptive αβTh17 Cells in Acute Respiratory Distress Syndrome

John T Li, Andrew C Melton, George Su, David E Hamm, Michael LaFemina, James Howard, Xiaohui Fang, Sudarshan Bhat, Kieu-My Huynh, Cecilia O'Kane, Rebecca J Ingram, Roshell R Muir, Daniel F McAuley, Michael A Matthay, Dean Sheppard

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)87-95
Number of pages9
JournalJournal of Immunology
Volume195
Issue number1
Early online date22 May 2015
DOIs
Publication statusPublished - Jul 2015

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  • Activities

    • 1 Invited talk

    Invited talk - The yin and yang of innate lymphoid cells

    Beckie Ingram (Speaker)

    09 Feb 2016

    Activity: Talk or presentation typesInvited talk

    Cite this

    Li, J. T., Melton, A. C., Su, G., Hamm, D. E., LaFemina, M., Howard, J., Fang, X., Bhat, S., Huynh, K-M., O'Kane, C., Ingram, R. J., Muir, R. R., McAuley, D. F., Matthay, M. A., & Sheppard, D. (2015). Unexpected Role for Adaptive αβTh17 Cells in Acute Respiratory Distress Syndrome. Journal of Immunology, 195(1), 87-95. https://doi.org/10.4049/jimmunol.1500054