CD56(bright)CD16(-) NK Cells Produce Adenosine through a CD38-Mediated Pathway and Act as Regulatory Cells Inhibiting Autologous CD4(+) T Cell Proliferation

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, we have here investigated the role of nucleotide-metabolizing 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 i) reverted pre-treating CD56brightCD16- NK cells with a CD38 inhibitor and ii) increased pre-treating 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 i) the observed reduced CD38/CD73 expression, ii) a peculiar ADO production kinetics and iii) 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 could be impaired during autoimmune/inflammatory diseases.