CpG ODN induced NK cell IFNγ production is positively regulated by IL-12 producing neutrophils and suppressed by IL-10 producing B cells (108.8)

Abstract

Abstract CpG-containing oligodeoxynucleotides (CpG ODN) stimulates spleen cells in vitro and induces IFNγ secretion mostly from NK cells, whereas purified NK cells are not stimulated by CpG ODN. IL-12 neutralization inhibits NK cell IFNγ production, and IL-12 knockout mouse spleen cells stimulated with CpG ODN produce very little IFNγ, indicating that IL-12 is required. Depletion of macrophages and DC has no effect, whereas neutrophil depletion dramatically decreases both IL-12 and IFNγ production by spleen cells, indicating that neutrophils are a key source of IL-12. NK cells in B cell-deficient mouse spleen secrete higher levels of IFNγ than wild type spleen cells, and B cell depletion enhances NK cell IFNγ production, indicating that B cells are suppressive. CD5+ B cells secrete IL-10 in response to CpG ODN. The neutralization of IL-10 increases IFNγ and IL-12 production by CpG ODN-stimulated spleen cells, and B cell-deficient splenocytes produce more IL-12 than WT splenocytes. Furthermore, exogenously added IL-10 effectively inhibits CpG ODN-induced IL-12 production by purified neutrophils, and IL-12/IL-18 induced stimulation of purified NK cells. Therefore, CD5+ B cells produce IL-10 and suppress CpG ODN-mediated NK cell IFNγ production by inhibiting neutrophil IL-12 production as well as by directly acting on activated NK cells themselves.