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

• Published in: The Journal of immunology (1950) Vol. 190; no. 3; pp. 948 - 960
• Main Authors: Crespo, María I, Zacca, Estefanía R, Núñez, Nicolás G, Ranocchia, Romina P, Maccioni, Mariana, Maletto, Belkys A, Pistoresi-Palencia, María C, Morón, Gabriel
• Format: Journal Article
• Language: English
• Published: United States 01.02.2013
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Antigen Presentation - drug effects; Antigen Presentation - immunology; Antigens - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Compartmentation; Cells, Cultured - immunology; Cytotoxicity, Immunologic; Dendritic Cells - drug effects; Dendritic Cells - immunology; Endosomes - immunology; Female; H-2 Antigens - immunology; Membrane Glycoproteins - drug effects; Membrane Glycoproteins - immunology; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin - immunology; Peptide Fragments - immunology; Phagosomes - immunology; Poly U - pharmacology; Proteasome Endopeptidase Complex - metabolism; Protein Transport; Receptors, Antigen, T-Cell, alpha-beta - immunology; SEC Translocation Channels; Spleen - immunology; Toll-Like Receptor 7 - drug effects; Toll-Like Receptor 7 - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1102725

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.