title: Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function.
abstract: During mouse cytomegalovirus (CMV) infection, a population of Ly49H(+) natural killer (NK) cells expands and is responsible for disease clearance through the induction of a "memory NK-cell response." Whether similar events occur in human CMV infection is unknown. In the present study, we characterized the kinetics of the NK-cell response to CMV reactivation in human recipients after hematopoietic cell transplantation. During acute infection, NKG2C(+) NK cells expanded and were potent producers of IFNγ. NKG2C(+) NK cells predominately expressed killer cell immunoglobulin-like receptor, and self-killer cell immunoglobulin-like receptors were required for robust IFNγ production. During the first year after transplantation, CMV reactivation induced a more mature phenotype characterized by an increase in CD56(dim) NK cells. Strikingly, increased frequencies of NKG2C(+) NK cells persisted and continued to increase in recipients who reactivated CMV, whereas these cells remained at low frequency in recipients without CMV reactivation. Persisting NKG2C(+) NK cells lacked NKG2A, expressed CD158b, preferentially acquired CD57, and were potent producers of IFNγ during the first year after transplantation. Recipients who reactivated CMV also expressed higher amounts of IFNγ, T-bet, and IL-15Rα mRNA transcripts. Our findings support the emerging concept that CMV-induced innate memory-cell populations may contribute to malignant disease relapse protection and infectious disease control long after transplantation.
authors.affiliation: Department of 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: Michelle
authors.initials: M
authors.lastname: Pitt
authors.forename: Julie
authors.initials: J
authors.lastname: Curtsinger
authors.forename: Xianghua
authors.initials: X
authors.lastname: Luo
authors.forename: Sandra
authors.initials: S
authors.lastname: Lopez-Vergès
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Daniel
authors.initials: D
authors.lastname: Weisdorf
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D018959:CD57 Antigens / Q000378:metabolism*; D015331:Cohort Studies; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D054340:Receptors, KIR / Q000235:genetics / Q000378:metabolism; D054343:Receptors, KIR2DL2 / Q000235:genetics / Q000378:metabolism; D054344:Receptors, KIR2DL3 / Q000235:genetics / Q000378:metabolism; D014184:Transplantation, Homologous; D014779:Virus Replication
chemical_list: D015415:Biomarkers; D018959:CD57 Antigens; C433932:KIR2DS2 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D012333:RNA, Messenger; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3; D007371:Interferon-gamma