Lung Dendritic Cells Drive Natural Killer Cytotoxicity in Chronic Obstructive Pulmonary Disease via IL-15Rα.

Finch DK, Stolberg VR, Ferguson J, Alikaj H, Kady MR, Richmond BW, Polosukhin VV, Blackwell TS, McCloskey L, Curtis JL, Freeman CM
Am J Respir Crit Care Med. 2018 198 (9): 1140-1150

PMID: 29676596 · PMCID: PMC6221577 · DOI:10.1164/rccm.201712-2513OC

RATIONALE - Lung natural killer cells (NKs) kill a greater percentage of autologous lung parenchymal cells in chronic obstructive pulmonary disease (COPD) than in nonobstructed smokers. To become cytotoxic, NKs require priming, typically by dendritic cells (DCs), but whether priming occurs in the lungs in COPD is unknown.

METHODS - We used lung tissue and in some cases peripheral blood from patients undergoing clinically indicated resections to determine in vitro killing of CD326 lung epithelial cells by isolated lung CD56 NKs. We also measured the cytotoxicity of unprimed blood NKs after preincubation with lung DCs. To investigate mechanisms of DC-mediated priming, we used murine models of COPD induced by cigarette smoke (CS) exposure or by polymeric immunoglobulin receptor (pIgR) deficiency, and blocked IL-15Rα (IL-15 receptor α subunit) trans-presentation by genetic and antibody approaches.

RESULTS - Human lung NKs killed isolated autologous lung epithelial cells; cytotoxicity was increased (P = 0.0001) in COPD, relative to smokers without obstruction. Similarly, increased lung NK cytotoxicity compared with control subjects was observed in CS-exposed mice and pIgR mice. Blood NKs both from smokers without obstruction and subjects with COPD showed minimal epithelial cell killing, but in COPD, preincubation with lung DCs increased cytotoxicity. NKs were primed by CS-exposed murine DCs in vitro and in vivo. Inhibiting IL-15Rα trans-presentation eliminated NK priming both by murine CS-exposed DCs and by lung DCs from subjects with COPD.

CONCLUSIONS - Heightened NK cytotoxicity against lung epithelial cells in COPD results primarily from lung DC-mediated priming via IL-15 trans-presentation on IL-15Rα. Future studies are required to test whether increased NK cytotoxicity contributes to COPD pathogenesis.

MeSH Terms (19)

Aged Animals Cigarette Smoking Cytotoxins Dendritic Cells Disease Models, Animal Epithelial Cells Female Flow Cytometry Humans Interleukin-15 Receptor alpha Subunit In Vitro Techniques Killer Cells, Natural Lymphocyte Activation Male Mice Mice, Inbred C57BL Prospective Studies Pulmonary Disease, Chronic Obstructive

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