title: Inflammation conditions mature dendritic cells to retain the capacity to present new antigens but with altered cytokine secretion function.
abstract: Dendritic cells (DCs) are directly activated by pathogen-associated molecular patterns (PAMPs) and undergo maturation. Mature DCs express high levels of MHC class II molecules ("signal 1"), upregulate T cell costimulatory receptors ("signal 2"), and secrete "signal 3" cytokines (e.g., IL-12). Mature DCs efficiently present Ags linked to the activating PAMP and prime naive T cells. However, mature DCs downregulate MHC II synthesis, which prevents them from presenting newly encountered Ags. DCs can also be indirectly activated by inflammatory mediators released during infection (e.g., IFN). Indirectly activated DCs mature but do not present pathogen Ags (as they have not encountered the pathogen) and do not provide signal 3. Therefore, although they are probably generated in large numbers upon infection or vaccination, indirectly activated DCs are considered to play little or no role in T cell immunity. In this article, we show that indirectly activated DCs retain their capacity to present Ags encountered after maturation in vivo. They can also respond to PAMPs, but the previous encounter of inflammatory signals alters their cytokine (signal 3) secretion pattern. This implies that the immune response elicited by a PAMP is more complex than predicted by the examination of the immunogenic features of directly activated DCs, and that underlying inflammatory processes can skew the immune response against pathogens. Our observations have important implications for the design of vaccines and for the understanding of the interactions between simultaneous infections, or of infection in the context of ongoing sterile inflammation.
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute of Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
authors.forename: Javier
authors.initials: J
authors.lastname: Vega-Ramos
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute of Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; Surgical Intensive Care Unit, Hotel Dieu, University Hospital of Nantes, 44093 Nantes, France; and.
authors.forename: Antoine
authors.initials: A
authors.lastname: Roquilly
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Young
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Justine D
authors.initials: JD
authors.lastname: Mintern
authors.affiliation: Department of Microbiology and Immunology, Doherty Institute of Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia j.villadangos@unimelb.edu.au.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Villadangos
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis
chemical_list: D016827:CD8 Antigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D010047:Ovalbumin; C545340:MARCH1 protein, mouse; D044767:Ubiquitin-Protein Ligases