Allogeneic bone marrow transplantation (allo-BMT) is a curative therapy for hematological malignancies, but is associated with significant complications, principally graftversus- 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-15Ra 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.
|Authors||Bunting, Mark D.; Varelias, Antiopi; Souza-Fonseca-Guimaraes, Fernando; Schuster, Iona S.; Lineburg, Katie E.; Kuns, Rachel D.; Fleming, Peter; Locke, Kelly R.; Huntington, Nicholas D.; Blazar, Bruce R.; Lane, Steven W.; Tey, Siok-Keen; MacDonald, Kelli P. A.; Smyth, Mark J.; Degli-Esposti, Mariapia A.; Hill, Geoffrey R.|
|Funding Body||National Health and Medical Research Council (NHMRC)|