title: TLR7 triggering with polyuridylic acid promotes cross-presentation in CD8α+ conventional dendritic cells by enhancing antigen preservation and MHC class I antigen permanence on the dendritic cell surface.
abstract: ssRNA can interact with dendritic cells (DCs) through binding to TLR7, inducing secretion of proinflammatory cytokines and type I IFN. Triggering TLR7 enhances cross-priming of CD8(+) T cells, which requires cross-presentation of exogenous Ag to DCs. However, how TLR triggering can affect Ag cross-presentation is still not clear. Using OVA as an Ag model, we observed that stimulation of TLR7 in DCs by polyuridylic acid (polyU), a synthetic ssRNA analog, generates a strong specific cytotoxic response in C57BL/6 mice. PolyU stimulate CD8α(+) DCs to cross-prime naive CD8(+) T cells in a type I IFN-dependent fashion. This enhanced cross-priming is accompanied by a higher density of OVA(256-264)/H-2K(b) complexes on CD8α(+) DCs treated with polyU, as well as by upregulation of costimulatory molecules and increased secretion of proinflammatory cytokines by DCs. Cross-priming of CD8(+) T cells by DCs treated with polyU requires proteasome and Ag translocation to cytosol through the Sec61 channel in DCs. The observed enhancement in OVA cross-presentation with polyU in DCs could be mediated by a limited Ag degradation in endophagosomal compartments and a higher permanence of OVA peptide/MHC class I complexes on DCs. These observations clearly reveal that key steps of Ag processing for cross-presentation can be modulated by TLR ligands, opening new avenues for understanding their mechanisms as adjuvants of the immune response.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba X5000HUA, Argentina.
authors.forename: María I
authors.initials: MI
authors.lastname: Crespo
authors.forename: Estefanía R
authors.initials: ER
authors.lastname: Zacca
authors.forename: Nicolás G
authors.initials: NG
authors.lastname: Núñez
authors.forename: Romina P
authors.initials: RP
authors.lastname: Ranocchia
authors.forename: Mariana
authors.initials: M
authors.lastname: Maccioni
authors.forename: Belkys A
authors.initials: BA
authors.lastname: Maletto
authors.forename: María C
authors.initials: MC
authors.lastname: Pistoresi-Palencia
authors.forename: Gabriel
authors.initials: G
authors.lastname: Morón
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002451:Cell Compartmentation; D002478:Cells, Cultured / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D011992:Endosomes / Q000276:immunology; D005260:Female; D006183:H-2 Antigens / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000276:immunology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology; D011072:Poly U / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D000069816:SEC Translocation Channels; D013154:Spleen / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000187:drug effects* / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C110366:OVA-8; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000069816:SEC Translocation Channels; C577653:SEC61A1 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C579127:ovalbumin (256-264); D011072:Poly U; D010047:Ovalbumin; D046988:Proteasome Endopeptidase Complex