title: Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population.
abstract: Knowledge of human NK cells is based primarily on conventional CD56(bright) and CD56(dim) NK cells from blood. However, most cellular immune interactions occur in lymphoid organs. Based on the coexpression of CD69 and CXCR6, we identified a third major NK cell subset in lymphoid tissues. This population represents 30-60% of NK cells in marrow, spleen, and lymph node but is absent from blood. CD69(+)CXCR6(+) lymphoid tissue NK cells have an intermediate expression of CD56 and high expression of NKp46 and ICAM-1. In contrast to circulating NK cells, they have a bimodal expression of the activating receptor DNAX accessory molecule 1. CD69(+)CXCR6(+) NK cells do not express the early markers c-kit and IL-7Rα, nor killer cell Ig-like receptors or other late-differentiation markers. After cytokine stimulation, CD69(+)CXCR6(+) NK cells produce IFN-γ at levels comparable to CD56(dim) NK cells. They constitutively express perforin but require preactivation to express granzyme B and exert cytotoxicity. After hematopoietic stem cell transplantation, CD69(+)CXCR6(+) lymphoid tissue NK cells do not exhibit the hyperexpansion observed for both conventional NK cell populations. CD69(+)CXCR6(+) NK cells constitute a separate NK cell population with a distinct phenotype and function. The identification of this NK cell population in lymphoid tissues provides tools to further evaluate the cellular interactions and role of NK cells in human immunity.
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden 2300 RC, the Netherlands; g.lugthart@lumc.nl.
authors.forename: Gertjan
authors.identifier: 0000-0002-3697-9316
authors.initials: G
authors.lastname: Lugthart
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden 2300 RC, the Netherlands;
authors.forename: Janine E
authors.identifier: 0000-0001-5322-7194
authors.initials: JE
authors.lastname: Melsen
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden 2300 RC, the Netherlands;
authors.forename: Carly
authors.identifier: 0000-0002-1618-6933
authors.initials: C
authors.lastname: Vervat
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden 2300 RC, the Netherlands;
authors.forename: Monique M
authors.initials: MM
authors.lastname: van Ostaijen-Ten Dam
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands; and.
authors.forename: Willem E
authors.identifier: 0000-0001-8313-3658
authors.initials: WE
authors.lastname: Corver
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
authors.forename: Dave L
authors.identifier: 0000-0002-1846-1193
authors.initials: DL
authors.lastname: Roelen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
authors.forename: Jeroen
authors.identifier: 0000-0002-9127-0385
authors.initials: J
authors.lastname: van Bergen
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden 2300 RC, the Netherlands;
authors.forename: Maarten J D
authors.identifier: 0000-0003-1600-4279
authors.initials: MJ
authors.lastname: van Tol
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden 2300 RC, the Netherlands;
authors.forename: Arjan C
authors.identifier: 0000-0002-6703-2993
authors.initials: AC
authors.lastname: Lankester
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden 2300 RC, the Netherlands;
authors.forename: Marco W
authors.identifier: 0000-0003-4391-6003
authors.initials: MW
authors.lastname: Schilham
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000276:immunology*; D008221:Lymphoid Tissue / Q000276:immunology*; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D000098862:T Lineage-Specific Activation Antigen 1; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D007371:Interferon-gamma; D037181:Lectins, C-Type; D055627:Natural Cytotoxicity Triggering Receptor 1; D000075744:Receptors, CXCR6; D019707:Receptors, Chemokine; D011991:Receptors, Virus; D000098862:T Lineage-Specific Activation Antigen 1; D000099192:CD69 Antigens; C106330:CXCR6 protein, human; C112260:NCR1 protein, human