title: Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation.
abstract: Interactions between killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands influence development of natural killer (NK) cell repertoire and response to infection, cancer, and allogeneic tissue. As KIRs and HLA class I molecules are highly polymorphic, clinical allogeneic hematopoietic cell transplantation is predicted to frequently involve KIR mismatch, and thus to provide a unique system for study of human NK cell receptor repertoire development. Eighteen leukemia patients undergoing HLA-matched transplantation and their donors were analyzed for KIR genotype. Ten of 13 HLA-identical donor-patient pairs were KIR mismatched and 3 were matched; all HLA-matched unrelated pairs were KIR mismatched. Reconstitution of recipient NK cell repertoire following transplantation was examined using flow cytometry and monoclonal antibodies specific for KIR and CD94:NKG2A. These data form 3 groups. Six to 9 months after transplantation, 8 patients (group 1) reconstituted an NK cell repertoire resembling that of their donor, and for KIR-mismatched transplants, distinct from the recipient before transplantation. In the first year after transplantation, 5 patients (group 2) exhibited a generally depressed frequency of KIR-expressing NK cells and concomitant high frequency of CD94:NKG2A expression. By 3 years after transplantation, the frequency of KIR-expressing NK cells had increased to donor values, in the 3 patients from group 2 analyzed for this period. The remaining 5 patients experienced severe clinical complications following transplantation and displayed unique features in their NK cell receptor reconstitution. These results demonstrate that a majority of HLA-matched hematopoietic cell transplantations involve KIR mismatch and reveal differences in NK cell repertoire having potential impact for immune responsiveness and transplantation outcome.
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Heather G
authors.initials: HG
authors.lastname: Shilling
authors.forename: Karina L
authors.initials: KL
authors.lastname: McQueen
authors.forename: Nathalie W
authors.initials: NW
authors.lastname: Cheng
authors.forename: Judith A
authors.initials: JA
authors.lastname: Shizuru
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
mesh_terms: D000208:Acute Disease; D000328:Adult; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D019070:Cell Lineage; D003602:Cytotoxicity, Immunologic; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics; D006648:Histocompatibility; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics* / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000628:therapy; D007951:Leukemia, Myeloid / Q000628:therapy; D008297:Male; D008875:Middle Aged; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D036102:Peripheral Blood Stem Cell Transplantation / Q000009:adverse effects; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell; D012074:Remission Induction; D018183:Transplantation Chimera; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D015703:Antigens, CD; D006680:HLA Antigens; C527054:KLRC1 protein, human; C497869:KLRD1 protein, human; D037181:Lectins, C-Type; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell