title: Conventional but not plasmacytoid dendritic cells foster the systemic virus-induced type I IFN response needed for efficient CD8 T cell priming.
abstract: Plasmacytoid dendritic cells (pDCs) are considered to be the principal type-I IFN (IFN-I) source in response to viruses, whereas the contribution of conventional DCs (cDCs) has been underestimated because, on a per-cell basis, they are not considered professional IFN-I-producing cells. We have investigated their respective roles in the IFN-I response required for CTL activation. Using a nonreplicative virus, baculovirus, we show that despite the high IFN-I-producing abilities of pDCs, in vivo cDCs but not pDCs are the pivotal IFN-I producers upon viral injection, as demonstrated by selective pDC or cDC depletion. The pathway involved in the virus-triggered IFN-I response is dependent on TLR9/MyD88 in pDCs and on stimulator of IFN genes (STING) in cDCs. Importantly, STING is the key molecule for the systemic baculovirus-induced IFN-I response required for CTL priming. The supremacy of cDCs over pDCs in fostering the IFN-I response required for CTL activation was also verified in the lymphocytic choriomeningitis virus model, in which IFN-β promoter stimulator 1 plays the role of STING. However, when the TLR-independent virus-triggered IFN-I production is impaired, the pDC-induced IFNs-I have a primary impact on CTL activation, as shown by the detrimental effect of pDC depletion and IFN-I signaling blockade on the residual lymphocytic choriomeningitis virus-triggered CTL response detected in IFN-β promoter stimulator 1(-/-) mice. Our findings reveal that cDCs play a major role in the TLR-independent virus-triggered IFN-I production required for CTL priming, whereas pDC-induced IFNs-I are dispensable but become relevant when the TLR-independent IFN-I response is impaired.
authors: Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain; mshervas@unav.es claude.leclerc@pasteur.fr.
authors: Sandra
authors: S
authors: Hervas-Stubbs
authors: Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain;
authors: Jose-Ignacio
authors: JI
authors: Riezu-Boj
authors: Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain;
authors: Uxua
authors: U
authors: Mancheño
authors: Inmunología y Genética Aplicada, S.A., Madrid 28037, Spain;
authors: Paloma
authors: P
authors: Rueda
authors: Inmunología y Genética Aplicada, S.A., Madrid 28037, Spain;
authors: Lissette
authors: L
authors: Lopez
authors: Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain;
authors: Diego
authors: D
authors: Alignani
authors: Division of Immunology and Immunotherapy, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain;
authors: Estefanía
authors: E
authors: Rodríguez-García
authors: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8147, Université René Descartes Paris V, Hôpital Necker, Paris F-75015, France;
authors: Nathalie
authors: N
authors: Thieblemont
authors: Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris F-75015, France; and INSERM, Unité 1041, Paris F-75015, France mshervas@unav.es claude.leclerc@pasteur.fr.
authors: Claude
authors: C
authors: Leclerc
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology* / Q000821:virology*; D005260:Female; D007370:Interferon Type I / Q000096:biosynthesis*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D017924:Nucleopolyhedroviruses / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000502:physiology
chemical_list: D007370:Interferon Type I; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9