Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury
Daniel R. Calabrese, … , Mark R. Looney, John R. Greenland
Daniel R. Calabrese, … , Mark R. Looney, John R. Greenland
Published December 8, 2020
Citation Information: J Clin Invest. 2021;131(3):e137047. https://doi.org/10.1172/JCI137047.
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Research Article Immunology Pulmonology

Natural killer cells activated through NKG2D mediate lung ischemia-reperfusion injury

Abstract

Pulmonary ischemia-reperfusion injury (IRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. IRI causes early mortality and has no effective therapies. While NK cells are innate lymphocytes capable of recognizing injured cells, their roles in acute lung injury are incompletely understood. Here, we demonstrated that NK cells were increased in frequency and cytotoxicity in 2 different IRI mouse models. We showed that NK cells trafficked to the lung tissue from peripheral reservoirs and were more mature within lung tissue. Acute lung ischemia-reperfusion injury was blunted in a NK cell–deficient mouse strain but restored with adoptive transfer of NK cells. Mechanistically, NK cell NKG2D receptor ligands were induced on lung endothelial and epithelial cells following IRI, and antibody-mediated NK cell depletion or NKG2D stress receptor blockade abrogated acute lung injury. In human lung tissue, NK cells were increased at sites of ischemia-reperfusion injury and activated NK cells were increased in prospectively collected human bronchoalveolar lavage in subjects with severe IRI. These data support a causal role for recipient peripheral NK cells in pulmonary IRI via NK cell NKG2D receptor ligation. Therapies targeting NK cells may hold promise in acute lung injury.

Authors

Daniel R. Calabrese, Emily Aminian, Benat Mallavia, Fengchun Liu, Simon J. Cleary, Oscar A. Aguilar, Ping Wang, Jonathan P. Singer, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Mary Nakamura, Lewis L. Lanier, Mark R. Looney, John R. Greenland

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Figure 2

NK cells in acutely injured lungs are more mature, cytotoxic, and activated.

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NK cells in acutely injured lungs are more mature, cytotoxic, and activa...
(A) As they mature, NK cells (CD3–NKp46+) gain CD27 and then CD11b with the most mature population described as CD27–CD11b+. There were no differences between HC (n = 5) and sham (S, n = 5) immature NK cell maturation states CD27–CD11b– (B, P = 0.1), CD27+CD11b– (C, P = 0.7), or CD27+CD11b+ (D, P = 0.6). In lungs subjected to HC, we found increased frequencies of mature (E, CD27–CD11b+) NK cells relative to dissociated sham lungs (P = 0.008) (F). The cytotoxic degranulation marker lysosomal-associated membrane protein (LAMP-1, CD107a) was measured on NK cells, with fluorescence histograms shown, representative of 6 experiments (G). CD107a+ NK cells were increased following HC (n = 6) relative to sham (n = 6) procedure (P = 0.002), and the mean fluorescence of CD017a was also increased on NK cells (H, P = 0.07). (I) The stress ligand receptor, NKG2D, was present on 99% of all NK cells, but had increased surface density after HC (J, n = 6, P = 0.005) compared with sham (n = 6). Box and whisker plots show individual data points bound by boxes at 25th and 75th percentiles and medians depicted with bisecting lines. Differences were determined by the Mann-Whitney U test.