title: Cell-Extrinsic MHC Class I Molecule Engagement Augments Human NK Cell Education Programmed by Cell-Intrinsic MHC Class I.
abstract: The effector potential of NK cells is counterbalanced by their sensitivity to inhibition by "self" MHC class I molecules in a process called "education." In humans, interactions between inhibitory killer immunoglobulin-like receptors (KIR) and human MHC (HLA) mediate NK cell education. In HLA-B(∗)27:05(+) transgenic mice and in patients undergoing HLA-mismatched hematopoietic cell transplantation (HCT), NK cells derived from human CD34(+) stem cells were educated by HLA from both donor hematopoietic cells and host stromal cells. Furthermore, mature human KIR3DL1(+) NK cells gained reactivity after adoptive transfer to HLA-B(∗)27:05(+) mice or bone marrow chimeric mice where HLA-B(∗)27:05 was restricted to either the hematopoietic or stromal compartment. Silencing of HLA in primary NK cells diminished NK cell reactivity, while acquisition of HLA from neighboring cells increased NK cell reactivity. Altogether, these findings reveal roles for cell-extrinsic HLA in driving NK cell reactivity upward, and cell-intrinsic HLA in maintaining NK cell education.
authors: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Jeanette E
authors: JE
authors: Boudreau
authors: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Xiao-Rong
authors: XR
authors: Liu
authors: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Zeguo
authors: Z
authors: Zhao
authors: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Aaron
authors: A
authors: Zhang
authors: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors: Leonard D
authors: LD
authors: Shultz
authors: Program in Molecular Medicine Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors: Dale L
authors: DL
authors: Greiner
authors: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors: Bo
authors: B
authors: Dupont
authors: Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: hsuk@mskcc.org.
authors: Katharine C
authors: KC
authors: Hsu
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D046528:Chimerism; D036101:Cord Blood Stem Cell Transplantation; D005110:Extracellular Space / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000235:genetics / Q000378:metabolism*; D019337:Hematologic Neoplasms / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007519:Isoantigens / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D054341:Receptors, KIR3DL1 / Q000378:metabolism*; D017154:Stromal Cells / Q000276:immunology*
chemical_list: D018952:Antigens, CD34; D001324:Autoantigens; C464936:HLA-B*27:05 antigen; D015796:HLA-B27 Antigen; D007519:Isoantigens; C515083:KIR3DL1 protein, human; D034741:RNA, Small Interfering; D054341:Receptors, KIR3DL1