GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity

Mark D. Bunting, Antiopi Varelias, Fernando Souza-Fonseca-Guimaraes, Iona S. Schuster, Katie E. Lineburg, Rachel D. Kuns, Peter Fleming, Kelly R. Locke, Nicholas D. Huntington, Bruce R. Blazar, Steven W. Lane, Siok Keen Tey, Kelli P A MacDonald, Mark J. Smyth, Mariapia A. Degli-Esposti, Geoffrey R. Hill

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16 Citations (Scopus)

Abstract

Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graft-versus-host disease (GVHD) and opportunistic infections. Natural killer (NK) cells mediate important innate immunity that provides a temporal bridge until the reconstruction of adaptive immunity. Here, we show that the development of GVHD after allo-BMT prevented NK-cell reconstitution, particularly within the maturing M1 and M2 NK-cell subsets in association with exaggerated activation, apoptosis, and autophagy. Donor T cells were critical in this process by limiting the availability of interleukin 15 (IL-15), and administration of IL-15/IL-15Rα or immune suppression with rapamycin could restore NK-cell reconstitution. Importantly, the NK-cell defect induced by GVHD resulted in the failure of NK-cell-dependent in vivo cytotoxicity and graft-versus-leukemia effects. Control of cytomegalovirus infection after allo-BMT was also impaired during GVHD. Thus, during GVHD, donor T cells compete with NK cells for IL-15 thereby inducing profound defects in NK-cell reconstitution that compromise both leukemia and pathogen-specific immunity.

Original languageEnglish
Pages (from-to)630-642
Number of pages13
JournalBlood
Volume129
Issue number5
DOIs
Publication statusPublished - 2 Feb 2017

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    Bunting, M. D., Varelias, A., Souza-Fonseca-Guimaraes, F., Schuster, I. S., Lineburg, K. E., Kuns, R. D., Fleming, P., Locke, K. R., Huntington, N. D., Blazar, B. R., Lane, S. W., Tey, S. K., MacDonald, K. P. A., Smyth, M. J., Degli-Esposti, M. A., & Hill, G. R. (2017). GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity. Blood, 129(5), 630-642. https://doi.org/10.1182/blood-2016-08-734020