Two distinct mechanisms for induction of dendritic cell apoptosis in response to intact Streptococcus pneumoniae.
Apoptotic dendritic cells (DCs) are ineffective at inducing immunity. Thus, parameters that regulate DC viability during a primary infection will help to determine the outcome of the subsequent immune response. In this regard, pathogens have developed strategies to promote DC apoptosis to counterbalance the nascent primary immune response. We demonstrate, using cultured bone marrow-derived DCs, that Streptococcus pneumoniae can induce DC apoptosis through two distinct mechanisms: 1) a rapid, caspase-independent mechanism of apoptosis induction, critically dependent on bacterial expression of pneumolysin, and 2) a delayed-onset, caspase-dependent mechanism of apoptosis induction associated with terminal DC maturation. Delayed-onset apoptosis does not require bacterial internalization, but rather is triggered by the interaction of bacterial subcapsular components and bone marrow-derived DC (likely Toll-like) receptors acting in a myeloid differentiation factor 88-dependent manner. In this regard, heavy polysaccharide encapsulation interferes with both DC maturation and apoptosis induction. In contrast, neither CD95/CD95 ligand interactions nor TNF-alpha appear to play a role in the delayed onset of apoptosis. These data are the first to define two mechanistically distinct pathways of DC apoptosis induction in response to an extracellular bacterium that likely have important consequences for the establishment of antibacterial immunity.
Colino
Jesus
J
Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Snapper
Clifford M
CM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000276:immunology*; D016667:Bacterial Capsules / Q000276:immunology; D001426:Bacterial Proteins; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D061945:Caspase Inhibitors; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000382:microbiology*; D004306:Dose-Response Relationship, Immunologic; D053222:Fas Ligand Protein; D006358:Hot Temperature; D016130:Immunophenotyping; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D010457:Peptidoglycan / Q000302:isolation & purification / Q000494:pharmacology; D010587:Phagocytosis / Q000276:immunology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology*; D013301:Streptolysins / Q000502:physiology; D013997:Time Factors; D019014:fas Receptor / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D001426:Bacterial Proteins; D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D010457:Peptidoglycan; D011971:Receptors, Immunologic; D013301:Streptolysins; D019014:fas Receptor; C032290:plY protein, Streptococcus pneumoniae