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 language | English |
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Pages (from-to) | 630-642 |
Number of pages | 13 |
Journal | Blood |
Volume | 129 |
Issue number | 5 |
DOIs | |
Publication status | Published or Issued - 2 Feb 2017 |
Keywords
- Animals
- Autophagy
- Bone Marrow Transplantation/adverse effects
- CD4-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/immunology
- Cell Line, Tumor
- Cytomegalovirus/immunology
- Cytomegalovirus Infections/complications
- Female
- Graft vs Host Disease/complications
- Humans
- Immunity, Innate
- Interleukin-15/immunology
- Killer Cells, Natural/immunology
- Leukemia/complications
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Transplantation, Homologous/adverse effects