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

Research output: Contribution to journalArticle

16 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.

LanguageEnglish
Pages630-642
Number of pages13
JournalBlood
Volume129
Issue number5
DOIs
Publication statusPublished - 2 Feb 2017
Externally publishedYes

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

Cite this

Bunting, M. D., Varelias, A., Souza-Fonseca-Guimaraes, F., Schuster, I. S., Lineburg, K. E., Kuns, R. D., ... Hill, G. R. (2017). GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity. Blood, 129(5), 630-642. https://doi.org/10.1182/blood-2016-08-734020