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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18 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
Externally publishedYes

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