Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation Journal Article


Authors: Yu, J.; Venstrom, J. M.; Liu, X. R.; Pring, J.; Hasan, R. S.; O'Reilly, R. J.; Hsu, K. C.
Article Title: Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function after T cell-depleted allogeneic hematopoietic cell transplantation
Abstract: Alloreactive natural killer (NK) cells are an important influence on hematopoietic stem cell transplantation (HSCT) outcome. In HLA-mismatched HSCT, alloreactivity occurs when licensed donor NK cells expressing inhibitory killer Ig-like receptors (KIR) for donor MHC class I ligands recognize the lack of the class I ligands in the mismatched recipient ("missing self"). Studies in HLA-matched HSCT, however, have also demonstrated improved outcome in patients lacking class I ligands for donor inhibitory KIR ("missing ligand"), indicating that classically nonlicensed donor NK cells expressing KIR for non-self MHC class I ligands may exhibit functional competence in HSCT. We examined NK function in 16 recipients of T cell-depleted allografts from HLA-identical or KIR-ligand matched donors after myeloablative therapy. After HSCT, nonlicensed NK cells expressing inhibitory KIR for non-self class I exhibit robust intracellular IFN-γ and cytotoxic response to target cells lacking cognate ligand, gradually becoming tolerized to self by day 100. These findings could not be correlated with cytokine environment or phenotypic markers of NK development, nor could they be attributed to non-KIR receptors such as CD94/NKG2A. These findings confirm that NK alloreactivity can occur in HLA-matched HSCT, where tolerance to self is either acquired by the stem cell-derived NK cell after exiting the bone marrow or where tolerance to self can be temporarily overcome. © 2009 by The American Society of Hematology.
Keywords: adolescent; adult; child; clinical article; preschool child; protein expression; school child; middle aged; leukemia; allograft; retrospective studies; transplantation, homologous; acute granulocytic leukemia; busulfan; fludarabine; cell maturation; fas antigen; cyclophosphamide; melphalan; hematopoietic stem cell transplantation; chronic myeloid leukemia; retrospective study; thiotepa; molecular mechanics; immunological tolerance; immunology; myeloablative conditioning; myelodysplastic syndrome; whole body radiation; donor; cellular immunity; gamma interferon; allogeneic hematopoietic stem cell transplantation; natural killer cell; killer cells, natural; killer cell immunoglobulin like receptor; natural killer cell receptor nkg2a; cytokine production; effector cell; receptors, kir; interferon-gamma; acute lymphocytic leukemia; graft rejection; t cell depletion; hla antigen; hla antigens; lymphocyte depletion; graft recipient; allotransplantation; myelodysplastic syndromes; lymphocyte function; transplantation tolerance; klrc1 protein, human; klrd1 protein, human; natural killer cell lectin like receptor subfamily c; natural killer cell lectin like receptor subfamily d; alloimmunity; immunity, cellular; nk cell lectin-like receptor subfamily c; nk cell lectin-like receptor subfamily d; self tolerance
Journal Title: Blood
Volume: 113
Issue: 16
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2009-04-16
Start Page: 3875
End Page: 3884
Language: English
DOI: 10.1182/blood-2008-09-177055
PUBMED: 19179302
PROVIDER: scopus
PMCID: PMC2670800
DOI/URL:
Notes: --- - "Cited By (since 1996): 21" - "Export Date: 30 November 2010" - "CODEN: BLOOA" - "Source: Scopus"
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MSK Authors
  1. Junli Yu
    4 Yu
  2. Katharine C Hsu
    149 Hsu
  3. Xiao-Rong Liu
    21 Liu
  4. Richard O'Reilly
    584 O'Reilly
  5. James Pring
    3 Pring
  6. Reenat S Hasan
    3 Hasan