Semimature Stage: A Checkpoint in a Dendritic Cell Maturation Program That Allows for Functional Reversion after Signal-Regulatory Protein-α Ligation and Maturation Signals

Abstract

CD47 on live cells actively engages signal-regulatory protein-α (SIRP-α) on phagocytes and delivers a negative signal that prevents their elimination. We evaluated the biological consequences of SIRP-α ligation on the dendritic cell (DC) response to maturation signals and the potential interplay with the IL-10/IL-10R inhibitory pathway. At first, CD47/SIRP-α allowed the generation of mature migratory DCs not producing IL-12, IFN-γ-inducible protein-10, and CCL19. Rather, they secreted neutrophils attracting chemokine CXCL5 and IL-1β, reflecting a partial block in functional DC maturation. Afterward, semimature DCs functionally regressed in an IL-10-independent fashion toward cells that retrieved the cardinal features of immature DCs: re-expression of CCR5, loss of DC-lysosome-associated membrane protein, high endocytosis, and impaired allostimulatory functions. The global gene expression profile of IL-10 and SIRP-α-ligated DC demonstrated two distinct molecular pathways. IL-10R and SIRP-α expression were reciprocally down-regulated by CD47 and IL-10, respectively. These results emphasize that the SIRP-α pathway might be part of the molecular machinery used by the DC to dampen or resolve an inflammatory response in an IL-10-independent manner.

Effects of porcine epidemic diarrhea virus on porcine monocyte-derived dendritic cells and intestinal dendritic cells

“…This may be a mechanism to prevent deleterious effects to DCs, because IL-10 induced by viruses can suppress or delay the host immune response (Redpath et al, 2001). Immature Mo-DCs activated by LPS produced high levels of IL-10, which has capacity to translocate class II MHC to the cell surface (Braun et al, 2006). These results may explain why SLA-II-DR increases when immature Mo-DCs are stimulated by LPS.…”

Rapid Dendritic Cell Activation and Resistance to Allotolerance Induction in Anti-CD154-Treated Mice Receiving CD47-Deficient Donor-Specific Transfusion

“…Cells were stained with fluorescein isothiocyanate (FITC)-conjugated anti-H-2D b (KH95), R-phycoerythrin (R-PE)-conjugated anti-mouse CD86 or I-A d , allophycocyanin (APC)-conjugated anti-mouse CD11c, and propidium iodide (4–color); or with FITC-conjugated anti-mouse CD11c, R-PE-conjugated anti-I-A d , APC-conjugated anti-mouse SIRPα, pacific blue-conjugated anti-mouse CD4, APC/cy7-conjugated CD8α, and propidium iodide (6–color). Nonspecific binding of labeled mAbs was blocked with 2.4G2 (rat anti-mouse FcγR mAb).…”

CD47 protein expression in acute myeloid leukemia: A tissue microarray-based analysis

“…Alternative pathogenetic mechanisms in addition to inhibition of phagocytosis have been proposed to contribute to a worse clinical outcome: CD47-SIRP␣ signaling on dendritic cells (DCs) impairs their T-cell allo-stimulatory capacity by blocking DC maturation [7], whilst the role of SIRP␣-independent triggering of CD47 to induce caspase-independent programmed cell death as not been unanimously confirmed [4,8].…”