title: Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization.
abstract: Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells.
  
  
  
  We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features.
  
  
  
  We performed multiparametric cytofluorimetric analysis of PD-1+NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays.
  
  
  
  We provide unequivocal evidence that PD-1 is highly expressed (PD-1bright) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56dimbut not CD56brightNK cells and is confined to fully mature NK cells characterized by the NKG2A-KIR+CD57+phenotype. Proportions of PD-1brightNK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their possible induction/expansion in tumor environments. Functional analysis revealed a reduced proliferative capability in response to cytokines, low degranulation, and impaired cytokine production on interaction with tumor targets.
  
  
  
  We have identified and characterized a novel subpopulation of human NK cells expressing high levels of PD-1. These cells have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma. They display low proliferative responses and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction.
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pesce
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Greppi
authors.affiliation: Department of Molecular and Translational Medicine, Brescia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tabellini
authors.affiliation: Department of Obstetrics and Gynecology, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Rampinelli
authors.affiliation: Department of Molecular and Translational Medicine, Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parolini
authors.affiliation: CRCM, Equipe Immunité et Cancer, Inserm, U1068, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.affiliation: Department of Immunology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy. Electronic address: alemoret@unige.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.affiliation: Department of Experimental Medicine, University of Genoa, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Marcenaro
mesh_terms: D015550:Cell Degranulation; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000502:physiology; D010051:Ovarian Neoplasms / Q000276:immunology; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*
chemical_list: D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: CD57(+) natural killer cells; Natural killer cells; cytomegalovirus; immune checkpoint; natural killer cell cytokine production; natural killer cell degranulation; natural killer cell proliferation; ovarian carcinoma; programmed death receptor; tumor escape