CD47 engagement inhibits cytokine production and maturation of human dendritic cells

Upon encounter with bacterial products, immature dendritic cells (iDCs) rel ease proinflammatory cytokines and develop into highly stimulatory mature D Cs, In the present study, we show that human monocyte-derived DCs functiona lly express the CD47 Ag, a thrombospondin receptor. Intact or F(ab')(2) of CD47 mAb suppress bacteria-induced production of IL-12, TNF-alpha, GM-CSF, and IL-6 by iDCs, 4N1K, a peptide derived from the CD47-binding site of thr ombospondin, also inhibits cytokine release. The inhibition of IL-12 and TN F-alpha is IL-10-independent inasmuch as IL-10 production is down-modulated by CD47 mAb and blocking IL-10 mAb fails to restore cytokine levels. CD47 ligation counteracts the phenotypic and functional maturation of iDCs in th at it prevents the up-regulation of costimulatory molecules, the loss of en docytic activity, and the acquisition of an increased capacity to stimulate T cell proliferation and IFN-gamma production. Interestingly, regardless o f CD47 mAb treatment during DC maturation, mature DC restimulated by solubl e CD40 ligand and IFN-gamma, to mimic DC/T interaction, produce less IL-12 and more IL-18 than iDCs, Finally, CD47 ligation on iDCs does not impair th eir capacity to phagocytose apoptotic cells. We conclude that following exp osure to microorganisms, CD47 ligation may limit the intensity and duration of the inflammatory response by preventing inflammatory cytokine productio n by iDCs and favoring their maintenance in an immature state.