title: CD56brightCD16- NK Cells Produce Adenosine through a CD38-Mediated Pathway and Act as Regulatory Cells Inhibiting Autologous CD4+ T Cell Proliferation.
abstract: Recent studies suggested that human CD56(bright)CD16(-) NK cells may play a role in the regulation of the immune response. Since the mechanism(s) involved have not yet been elucidated, in the present study we have investigated the role of nucleotide-metabolizing enzymes that regulate the extracellular balance of nucleotides/nucleosides and produce the immunosuppressive molecule adenosine (ADO). Peripheral blood CD56(dim)CD16(+) and CD56(bright)CD16(-) NK cells expressed similar levels of CD38. CD39, CD73, and CD157 expression was higher in CD56(bright)CD16(-) than in CD56(dim)CD16(+) NK cells. CD57 was mostly expressed by CD56(dim)CD16(+) NK cells. CD203a/PC-1 expression was restricted to CD56(bright)CD16(-) NK cells. CD56(bright)CD16(-) NK cells produce ADO and inhibit autologous CD4(+) T cell proliferation. Such inhibition was 1) reverted pretreating CD56(bright)CD16(-) NK cells with a CD38 inhibitor and 2) increased pretreating CD56(bright)CD16(-) NK cells with a nucleoside transporter inhibitor, which increase extracellular ADO concentration. CD56(bright)CD16(-) NK cells isolated from the synovial fluid of juvenile idiopathic arthritis patients failed to inhibit autologous CD4(+) T cell proliferation. Such functional impairment could be related to 1) the observed reduced CD38/CD73 expression, 2) a peculiar ADO production kinetics, and 3) a different expression of ADO receptors. In contrast, CD56(bright)CD16(-) NK cells isolated from inflammatory pleural effusions display a potent regulatory activity. In conclusion, CD56(bright)CD16(-) NK cells act as "regulatory cells" through ADO produced by an ectoenzymes network, with a pivotal role of CD38. This function may be relevant for the modulation of the immune response in physiological and pathological conditions, and it could be impaired during autoimmune/inflammatory diseases.
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, 16148 Genoa, Italy; fabiomorandi@ospedale-gaslini.ge.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Morandi
authors.affiliation: Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Turin, Turin 10126, Italy; Immunologia dei Trapianti, Città della Salute e della Scienza, Turin 10126, Italy;
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Horenstein
authors.affiliation: Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Turin, Turin 10126, Italy;
authors.forename: Antonella
authors.initials: A
authors.lastname: Chillemi
authors.affiliation: Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Turin, Turin 10126, Italy;
authors.forename: Valeria
authors.initials: V
authors.lastname: Quarona
authors.affiliation: Unità Operativa Pediatria II - Reumatologia, Istituto Giannina Gaslini, Genoa 16148, Italy;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Chiesa
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, 21100 Varese, Italy; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Imperatori
authors.affiliation: Department of Surgical and Morphological Sciences, University of Insubria, 21100 Varese, Italy; and Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zanellato
authors.affiliation: Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Mortara
authors.affiliation: Unità Operativa Pediatria II - Reumatologia, Istituto Giannina Gaslini, Genoa 16148, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, 16148 Genoa, Italy;
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
authors.affiliation: Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Turin, Turin 10126, Italy; Immunologia dei Trapianti, Città della Salute e della Scienza, Turin 10126, Italy;
authors.forename: Fabio
authors.initials: F
authors.lastname: Malavasi
mesh_terms: D015720:5'-Nucleotidase / Q000096:biosynthesis; D036541:ADP-ribosyl Cyclase / Q000096:biosynthesis; D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000241:Adenosine / Q000096:biosynthesis*; D015703:Antigens, CD / Q000096:biosynthesis; D001081:Apyrase / Q000096:biosynthesis; D001171:Arthritis, Juvenile / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019002:CD56 Antigen / Q000235:genetics*; D018959:CD57 Antigens / Q000096:biosynthesis; D049109:Cell Proliferation / Q000235:genetics; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017452:Receptors, IgG / Q000276:immunology; D013582:Synovial Fluid / Q000166:cytology
chemical_list: D015703:Antigens, CD; D019002:CD56 Antigen; D018959:CD57 Antigens; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C522918:NCAM1 protein, human; D017452:Receptors, IgG; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D036541:ADP-ribosyl Cyclase; C087521:ADP-ribosyl cyclase 2; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine