Inhibitory effects of apoptotic cell ingestion upon endotoxin-driven myeloid dendritic cell maturation.
Dendritic cells (DCs) are the sentinels of the immune system, able to interact with both naive and memory T cells. The recent observation that DCs can ingest cells dying by apoptosis has raised the possibility that DCs may, in fact, present self-derived Ags, initiating both autoimmunity and tumor-specific responses, especially if associated with appropriate danger signals. Although the process of ingestion of apoptotic cells has not been shown to induce DC maturation, the exact fate of these phagocytosing DCs remains unclear. In this paper we demonstrate that DCs that ingest apoptotic cells are able to produce TNF-alpha but have a diminished ability to produce IL-12 in response to external stimuli, a property that corresponds to a failure to up-regulate CD86. By single-cell analysis we demonstrate that these inhibitory effects are restricted to those DCs that have engulfed apoptotic cells, with bystander DCs remaining unaffected. These changes were independent of the production of anti-inflammatory cytokines TGF-beta1 and IL-10 and corresponded with a diminished capacity to stimulate naive T cells. Thus, the ingestion of apoptotic cells is not an immunologically null event but is capable of modulating DC maturation. These results have important implications for our understanding of the role of clearance of dying cells by DCs not only in the normal resolution of inflammation but also in control of subsequent immune responses to apoptotic cell-derived Ags.
Stuart
Lynda M
LM
Medical Research Council Center for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, United Kingdom. lynda.stuart@ed.ac.uk
Lucas
Mark
M
Simpson
Cathy
C
Lamb
Jonathan
J
Savill
John
J
Lacy-Hulbert
Adam
A
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D051940:B7-2 Antigen; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000276:immunology*; D010587:Phagocytosis; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10