title: Phenotypically distinct helper NK cells are required for gp96-mediated anti-tumor immunity.
abstract: A number of Heat Shock Proteins (HSPs), in the extracellular environment, are immunogenic. Following cross-presentation of HSP-chaperoned peptides by CD91(+) antigen presenting cells (APCs), T cells are primed with specificity for the derivative antigen-bearing cell. Accordingly, tumor-derived HSPs are in clinical trials for cancer immunotherapy. We investigate the role of NK cells in gp96-mediated anti-tumor immune responses given their propensity to lyse tumor cells. We show that gp96-mediated rejection of tumors requires a unique and necessary helper role in NK cells. This helper role occurs during the effector phase of the anti-tumor immune response and is required for T cell and APC function. Gp96 activates NK cells indirectly via APCs to a phenotype distinct from NK cells activated by other mechanisms such as IL-2. While NK cells have both lytic and cytokine producing properties, we show that gp96 selectively activates cytokine production in NK cells, which is important in the HSP anti-tumor immune response, and leaves their cytotoxic capacity unchanged.
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 USA.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Sedlacek
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 USA.
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Kinner-Bibeau
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261 USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Binder
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology; D006360:Heat-Shock Proteins / Q000276:immunology* / Q000627:therapeutic use; D006801:Humans; D007111:Immunity, Cellular; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D018832:Molecular Chaperones; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D006360:Heat-Shock Proteins; D007376:Interleukin-2; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D010455:Peptides; C053387:endoplasmin