title: NK cell education after allogeneic transplantation: dissociation between recovery of cytokine-producing and cytotoxic functions.
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.
authors.affiliation: Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Bree
authors.initials: B
authors.lastname: Foley
authors.forename: Sarah
authors.initials: S
authors.lastname: Cooley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.forename: Julie
authors.initials: J
authors.lastname: Curtsinger
authors.forename: Xianghua
authors.initials: X
authors.lastname: Luo
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology*; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000276:immunology* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D019409:Interleukin-15 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008212:Lymphocyte Depletion; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D054340:Receptors, KIR / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D019409:Interleukin-15; D052118:Lysosomal-Associated Membrane Protein 1; D054340:Receptors, KIR; D007371:Interferon-gamma