GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity
- Bunting, MD; Varelias, A; Souza-Fonseca-Guimaraes, F; Schuster, IS; Lineburg, KE; Kuns, RD; Fleming, P; Locke, KR; Huntington, ND; Blazar, BR; Lane, SW; Tey, SK; MacDonald, KP; Smyth, MJ; Degli-Esposti, MA; Hill, GR;
Publication Year 2017-12-07, Volume 129, Issue #5, Page 630-642
- Journal Title
- Publication Type
- Journal Article
- 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 IL-15, and administration of IL-15/IL-15Ralpha 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.
- WEHI Research Division(s)
- Molecular Immunology
- PubMed ID
- Publisher's Version
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Creation Date: 2017-05-26 03:11:42Last Modified: 2017-05-26 03:16:25