Proinflammatory molecules, including IFN-γ and IL-12, play a crucial role in the elimination of causative agents. To allow healing, potent anti-inflammatory processes are required to down-regulate the inflammatory response. In this study, we first show that CD47/integrin-associated protein, a ubiquitous multispan transmembrane protein highly expressed on T cells, interacts with signal-regulator protein (SIRP)-α, an immunoreceptor tyrosine-based inhibition motif-containing molecule selectively expressed on myelomonocytic cells, and next demonstrate that this pair of molecules negatively regulates human T and dendritic cell (DC) function. CD47 ligation by CD47 mAb or L-SIRP-α transfectants inhibits IL-12R expression and down-regulates IL-12 responsiveness of activated CD4+ and CD8+ adult T cells without affecting their response to IL-2. Human CD47-Fc fusion protein binds SIRP-α expressed on immature DC and mature DC. SIRP-α engagement by CD47-Fc prevents the phenotypic and functional maturation of immature DC and still inhibits cytokine production by mature DC. Finally, in allogeneic MLR between mDC and naive T cells, CD47-Fc decreases IFN-γ production after priming and impairs the development of a Th1 response. Therefore, CD47 on T cells and its cognate receptor SIRP-α on DC define a novel regulatory pathway that may be involved in the maintenance of homeostasis by preventing the escalation of the inflammatory immune response.