title: Phenotypic and functional activation of hyporesponsive KIRnegNKG2Aneg human NK-cell precursors requires IL12p70 provided by Poly(I:C)-matured monocyte-derived dendritic cells.
abstract: A functionally responsive natural killer (NK)-cell repertoire requires the acquisition of inhibitory NKG2A and killer immunoglobulin-like receptors (KIR) through pathways that remain undefined. Functional donor NK cells expressing KIRs for non-self class I MHC ligands contribute to a positive outcome after allogeneic hematopoietic stem cell transplantation (alloHSCT) by targeting HLA-matched recipient leukemic cells. Insofar as circulating donor conventional dendritic cells (DC) reconstitute with comparable kinetics with donor NK cells after alloHSCT, we used hyporesponsive KIRnegNKG2Aneg precursor cells to evaluate how specific DC subtypes generate a functionally active NK-cell repertoire. Both monocyte-derived DCs (moDC) and Langerhans-type DCs (LC) induce KIRnegNKG2Aneg precursor cells to express the inhibitory receptors NKG2A and KIR, without requiring cell proliferation. Poly(I:C)-matured moDCs significantly augmented the expression of NKG2A, but not KIR, in an IL12p70-dependent manner. Although all DC-stimulated KIRnegNKG2Aneg cells were able to acquire cytolytic activity against class I MHC-negative targets, the ability to secrete IFNγ was restricted to cells that were stimulated by IL12p70-producing, poly(I:C)-matured moDCs. This critical ability of poly(I:C)-matured moDCs to provide IL12p70 to developing KIRnegNKG2Aneg precursors results in a dom4inant, multifunctional, NKG2Apos NK-cell population that is capable of both cytolysis and IFNγ production. Poly(I:C)-matured moDCs are, therefore, the most effective conventional DC subtype for generating a functionally competent NK-cell repertoire by an IL12p70-dependent mechanism.
authors.affiliation: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. currans1@mskcc.org.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Curran
authors.affiliation: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Romano
authors.affiliation: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kennedy
authors.affiliation: Laboratory of Natural Killer Cell Biology, Immunology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. Adult Bone Marrow Transplantation Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Hsu
authors.affiliation: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. Adult Bone Marrow Transplantation Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: James W
authors.initials: JW
authors.lastname: Young
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007121:Immunocompetence / Q000276:immunology; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000378:metabolism*; D011070:Poly I-C / Q000276:immunology; D054340:Receptors, KIR / Q000378:metabolism
chemical_list: D016207:Cytokines; D055654:NK Cell Lectin-Like Receptor Subfamily C; D054340:Receptors, KIR; D018664:Interleukin-12; D007371:Interferon-gamma; D011070:Poly I-C