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Cytokine complex-expanded natural killer cells improve allogeneic lung transplant function via depletion of donor dendritic cells


Jungraithmayr, Wolfgang; Codarri, Laura; Bouchaud, Gregory; Krieg, Carsten; Boyman, Onur; Gyülvészi, Gabor; Becher, Burkhard; Weder, Walter; Münz, Christian (2013). Cytokine complex-expanded natural killer cells improve allogeneic lung transplant function via depletion of donor dendritic cells. American Journal of Respiratory and Critical Care Medicine, 187(12):1349-1359.

Abstract

RATIONALE: Natural killer (NK) cells are innate lymphocytes that target virus-infected and tumor cells. Much less is known about their ability to limit adaptive immune responses. OBJECTIVES: Thus, we investigated to what extent NK cells can influence mouse lung allograft rejection. METHODS: For this purpose, we employed an orthotopic lung transplantation model in mice. MEASUREMENTS AND MAIN RESULTS: We demonstrate here that NK cells infiltrate mouse lung allografts before T cells and thereby diminished allograft inflammation, and that NK-cell deficiency enhanced allograft rejection. In contrast, expansion of recipient NK cells through IL-15/IL-15Rα complex treatment resulted in decreased T-cell infiltration and alloreactive T-cell priming as well as improved function of the allogeneic lung transplant. Only perforin-competent, but not perforin-deficient, NK cells were able to transfer these beneficial effects into transplanted NK cell-deficient IL-15Rα(-/-) mice. These NK cells killed allogeneic dendritic cells (DCs) in vitro and significantly decreased the number of allogeneic DCs in transplanted lungs in vivo. Furthermore, DC-depleted lung allografts presented decreased signs of rejection. CONCLUSIONS: These results suggest that NK cells favor allograft acceptance by depleting donor-derived DCs, which otherwise would prime alloreactive T-cell responses. Thus, conditioning regimens that augment NK-cell reactivity should be clinically explored to prepare lung allograft recipients.

Abstract

RATIONALE: Natural killer (NK) cells are innate lymphocytes that target virus-infected and tumor cells. Much less is known about their ability to limit adaptive immune responses. OBJECTIVES: Thus, we investigated to what extent NK cells can influence mouse lung allograft rejection. METHODS: For this purpose, we employed an orthotopic lung transplantation model in mice. MEASUREMENTS AND MAIN RESULTS: We demonstrate here that NK cells infiltrate mouse lung allografts before T cells and thereby diminished allograft inflammation, and that NK-cell deficiency enhanced allograft rejection. In contrast, expansion of recipient NK cells through IL-15/IL-15Rα complex treatment resulted in decreased T-cell infiltration and alloreactive T-cell priming as well as improved function of the allogeneic lung transplant. Only perforin-competent, but not perforin-deficient, NK cells were able to transfer these beneficial effects into transplanted NK cell-deficient IL-15Rα(-/-) mice. These NK cells killed allogeneic dendritic cells (DCs) in vitro and significantly decreased the number of allogeneic DCs in transplanted lungs in vivo. Furthermore, DC-depleted lung allografts presented decreased signs of rejection. CONCLUSIONS: These results suggest that NK cells favor allograft acceptance by depleting donor-derived DCs, which otherwise would prime alloreactive T-cell responses. Thus, conditioning regimens that augment NK-cell reactivity should be clinically explored to prepare lung allograft recipients.

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14 citations in Web of Science®
14 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2013
Deposited On:13 Dec 2013 15:32
Last Modified:05 Apr 2016 17:15
Publisher:American Thoracic Society
ISSN:1073-449X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1164/rccm.201209-1749OC
PubMed ID:23590269

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