title: Adaptive Natural Killer Cell and Killer Cell Immunoglobulin-Like Receptor-Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated with Protection against Cytomegalovirus Reactivation after Allogeneic Donor Hematopoietic Cell Transplantation.
abstract: Cytomegalovirus (CMV) reactivates in >30% of CMV-seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of natural killer (NK) cells expressing NKG2C, CD57, and inhibitory killer cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation after HCT. These NK cells persist after the resolution of infection and display "adaptive" or memory properties. Despite these findings, the differential impact of persistent/inactive versus reactivated CMV on NK versus T cell maturation after HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pretransplantation CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an adaptive phenotype (NKG2C(+)CD57(+)). Compared with CMV-seronegative recipients, those who reactivated CMV had the highest adaptive cell frequencies, whereas intermediate frequencies were observed in CMV-seropositive recipients harboring persistent/nonreplicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV-seropositive recipients of sibling but not UCB grafts and were correlated with lower rates of CMV reactivation (sibling 33% versus UCB 51%; P < .01). These data suggest that persistent/nonreplicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation.
authors.affiliation: Blood and Marrow Transplant Program, Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Davis
authors.affiliation: Blood and Marrow Transplant Program, Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Cooley
authors.affiliation: Blood and Marrow Transplant Program, Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Frank
authors.initials: F
authors.lastname: Cichocki
authors.affiliation: Blood and Marrow Transplant Program, Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Martin
authors.initials: M
authors.lastname: Felices
authors.affiliation: Blood and Marrow Transplant Program, Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Rose
authors.initials: R
authors.lastname: Wangen
authors.affiliation: Division of Biostatistics, School of Public Health and Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Luo
authors.affiliation: Blood and Marrow Transplant Program, Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Todd E
authors.initials: TE
authors.lastname: DeFor
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.affiliation: Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brunstein
authors.affiliation: Blood and Marrow Transplant Program, Department of Pediatric, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Blood and Marrow Transplant Program, Department of Pediatric, University of Minnesota, Minneapolis, Minnesota.
authors.forename: John E
authors.initials: JE
authors.lastname: Wagner
authors.affiliation: Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.affiliation: Structural Biology and Microbiology and Immunology, Stanford University, Stanford, California.
authors.forename: Amir
authors.initials: A
authors.lastname: Horowitz
authors.affiliation: Structural Biology and Microbiology and Immunology, Stanford University, Stanford, California.
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.affiliation: Structural Biology and Microbiology and Immunology, Stanford University, Stanford, California.
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
authors.affiliation: Blood and Marrow Transplant Program, Department of Pediatric, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address: mille011@umn.edu.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
mesh_terms: D064591:Allografts; D036101:Cord Blood Stem Cell Transplantation; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007694:Killer Cells, Natural; D008297:Male; D054340:Receptors, KIR / Q000276:immunology*; D035781:Siblings; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D054340:Receptors, KIR
keywords: Clinical outcomes; Cytomegalovirus reactivation; Natural killer cells; Transplantation