NK cell education after allogeneic transplantation: dissociation between recovery of cytokine-producing and cytotoxic functions

Blood. 2011 Sep 8;118(10):2784-92. doi: 10.1182/blood-2011-04-347070. Epub 2011 Jul 14.

Abstract

Natural killer (NK) cells mediate GVL effects after allogeneic hematopoietic cell transplantation (allo-HCT) by the production of inflammatory cytokines and by direct target lysis. The acquisition of both functions was presumed to be developmentally linked, but this linkage remained unstudied after allo-HCT. We tested the cytokine production and degranulation of reconstituting NK cells after adult unrelated donor or umbilical cord blood grafting. Recipients of T cell-depleted transplants, receiving no immune suppression, showed diminished NK cell degranulation. In contrast, degranulation was normal or increased after T-cell replete transplants given with immune suppression. Strikingly, target cell-induced IFNγ production was markedly diminished in all transplant settings, especially with T cell-depleted or naive T cell-containing umbilical cord blood grafts, suggesting a role for T cells in NK education. Although degranulation was similar in the KIR(+) and KIR(-) populations that coexpressed NKG2A, target cell-induced IFNγ production was limited to the subset of NK cells expressing KIR inhibited by self-ligands. Thus, cytokine production and cytotoxic function do not consistently coexist in NK cells reconstituting after allo-HCT. Exposure to IL-15 rapidly increased target-inducible IFNγ production, indicative of IL-15's potential as a therapeutic tool to enhance NK cell function to protect against infection and relapse after allo-HCT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apoptosis / immunology*
  • Flow Cytometry
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / metabolism
  • Hematologic Neoplasms / immunology*
  • Hematologic Neoplasms / therapy
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Interferon-gamma / metabolism*
  • Interleukin-15 / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Depletion
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Receptors, KIR / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transplantation, Homologous

Substances

  • Interleukin-15
  • Lysosomal-Associated Membrane Protein 1
  • Receptors, KIR
  • Interferon-gamma