TY - JOUR
T1 - CD56brightCD16- NK cells produce adenosine through a CD38-mediated pathway and act as regulatory cells inhibiting autologous CD4+ T cell proliferation
AU - Morandi, Fabio
AU - Horenstein, Alberto L.
AU - Chillemi, Antonella
AU - Quarona, Valeria
AU - Chiesa, Sabrina
AU - Imperatori, Andrea
AU - Zanellato, Silvia
AU - Mortara, Lorenzo
AU - Gattorno, Marco
AU - Pistoia, Vito
AU - Malavasi, Fabio
PY - 2015/8/1
Y1 - 2015/8/1
N2 - Recent studies suggested that human CD56brightCD16- 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 nucleotidemetabolizing enzymes that regulate the extracellular balance of nucleotides/nucleosides and produce the immunosuppressive molecule adenosine (ADO). Peripheral blood CD56dimCD16+ and CD56brightCD16- NK cells expressed similar levels of CD38. CD39, CD73, and CD157 expression was higher in CD56brightCD16- than in CD56dimCD16+ NK cells. CD57 was mostly expressed by CD56dimCD16+ NK cells. CD203a/PC-1 expression was restricted to CD56brightCD16- NK cells. CD56brightCD16- NK cells produce ADO and inhibit autologous CD4+ T cell proliferation. Such inhibition was 1) reverted pretreating CD56brightCD16- NK cells with a CD38 inhibitor and 2) increased pretreating CD56brightCD16- NK cells with a nucleoside transporter inhibitor, which increase extracellular ADO concentration. CD56brightCD16- 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, CD56brightCD16- NK cells isolated from inflammatory pleural effusions display a potent regulatory activity. In conclusion, CD56brightCD16- 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.
AB - Recent studies suggested that human CD56brightCD16- 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 nucleotidemetabolizing enzymes that regulate the extracellular balance of nucleotides/nucleosides and produce the immunosuppressive molecule adenosine (ADO). Peripheral blood CD56dimCD16+ and CD56brightCD16- NK cells expressed similar levels of CD38. CD39, CD73, and CD157 expression was higher in CD56brightCD16- than in CD56dimCD16+ NK cells. CD57 was mostly expressed by CD56dimCD16+ NK cells. CD203a/PC-1 expression was restricted to CD56brightCD16- NK cells. CD56brightCD16- NK cells produce ADO and inhibit autologous CD4+ T cell proliferation. Such inhibition was 1) reverted pretreating CD56brightCD16- NK cells with a CD38 inhibitor and 2) increased pretreating CD56brightCD16- NK cells with a nucleoside transporter inhibitor, which increase extracellular ADO concentration. CD56brightCD16- 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, CD56brightCD16- NK cells isolated from inflammatory pleural effusions display a potent regulatory activity. In conclusion, CD56brightCD16- 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.
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U2 - 10.4049/jimmunol.1500591
DO - 10.4049/jimmunol.1500591
M3 - Article
C2 - 26091716
AN - SCOPUS:84937714187
VL - 195
SP - 965
EP - 972
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -