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Ligation and Maturation Signals1
,
* Immunoregulation Laboratory, Centre hospitalier de l’Université de Montréal Research Center, University of Montreal, Montreal, Canada;
Serono Pharmaceutical Research Institute, Geneva, Switzerland;
Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; and
Laboratory for Allergy Transcriptome, RIKEN Research Center for Allergy and Immunology, Tokyo, Japan
CD47 on live cells actively engages signal-regulatory protein-
(SIRP-) on phagocytes and delivers a negative signal that prevents their elimination. We evaluated the biological consequences of SIRP- 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- allowed the generation of mature migratory DCs not producing IL-12, IFN-
-inducible protein-10, and CCL19. Rather, they secreted neutrophils attracting chemokine CXCL5 and IL-1
, 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--ligated DC demonstrated two distinct molecular pathways. IL-10R and SIRP- expression were reciprocally down-regulated by CD47 and IL-10, respectively. These results emphasize that the SIRP- 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Canadian Institutes for Health Research (MOP-44090). D.B. was sponsored by the Association pour la Recherche sur le Cancer.
2 Current address: Institut Pasteur, Paris, France.
3 Address correspondence and reprint requests to Dr. Marika Sarfati, Laboratoire d’Immunorégulation (M4211K), Centre de Recherche du Centre hospitalier de l’Université de Montréal, Hôpital Notre-Dame, 1560 Sherbrooke Est, Montréal H2L4M1, Québec, Canada. E-mail address: m.sarfati{at}umontreal.ca
4 Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; SIRP, signal-regulatory protein; mDC, mature DC; SAC, Staphylococcus aureus Cowan I strain; SDF, stromal cell-derived factor; LN, lymph node; IP-10, IFN--inducible protein-10; LAMP, lysosome-associated membrane protein.
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