Conventional but not plasmacytoid dendritic cells foster the systemic virus-induced type I IFN response needed for efficient CD8 T cell priming

• Published in: The Journal of immunology (1950) 2014-08, Vol.193 (3), p.1151-1161
• Main Authors: Hervas-Stubbs, Sandra, Riezu-Boj, Jose-Ignacio, Mancheño, Uxua, Rueda, Paloma, Lopez, Lissette, Alignani, Diego, Rodríguez-García, Estefanía, Thieblemont, Nathalie, Leclerc, Claude
• Format: Article
• Language: English
• Subjects: Animals; Baculovirus; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - virology; Cytotoxicity, Immunologic; Dendritic Cells - classification; Dendritic Cells - immunology; Dendritic Cells - virology; Female; Immune Regulation; Interferon Type I - biosynthesis; Lymphocytic choriomeningitis virus; Lymphocytic choriomeningitis virus - immunology; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Myeloid Differentiation Factor 88 - physiology; Nucleopolyhedrovirus - immunology; Signal Transduction - immunology; Toll-Like Receptor 9 - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1301440

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.