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.
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The authors acknowledge Michelle Teng for her critical reading of the manuscript. This work was supported by research grants from the National Health and Medical Research Council (NHandMRC). F.S.-F.-G. was supported by a NHandMRC Early Career Research Fellowship and National Breast Cancer Foundation Fellowship. S.W.L. was supported by a NHandMRC Career Development Fellowship. M.A.D.-E. was a NHandMRC Principal Research Fellow. M.J.S. and G.R.H. were NHandMRC Senior Principal Research Fellows. G.R.H. was a QLD Health Senior Clinical Research Fellow. B.R.B. was supported by National Institutes of Health National Cancer Institute grant R01 CA72669.