Conventional Dendritic Cells Confer Protection against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling

Franz Puttur, Marcela Francozo, Gülhas Solmaz, Carlos Bueno, Marc Lindenberg, Melanie Gohmert, Maxine Swallow, Dejene Tufa, Roland Jacobs, Stefan Lienenklaus, Anja A. Kühl, Lisa Borkner, Luka Cicin-Sain, Bernard Holzmann, Hermann Wagner, Luciana Berod, Tim Sparwasser

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cytomegalovirus (CMV) is an opportunistic virus severely infecting immunocompromised individuals. In mice, endosomal Toll-like receptor 9 (TLR9) and downstream myeloid differentiation factor 88 (MyD88) are central to activating innate immune responses against mouse CMV (MCMV). In this respect, the cell-specific contribution of these pathways in initiating anti-MCMV immunity remains unclear. Using transgenic mice, we demonstrate that TLR9/MyD88 signaling selectively in CD11c+ dendritic cells (DCs) strongly enhances MCMV clearance by boosting natural killer (NK) cell CD69 expression and IFN-γ production. In addition, we show that in the absence of plasmacytoid DCs (pDCs), conventional DCs (cDCs) promote robust NK cell effector function and MCMV clearance in a TLR9/MyD88-dependent manner. Simultaneously, cDC-derived IL-15 regulates NK cell degranulation by TLR9/MyD88-independent mechanisms. Overall, we compartmentalize the cellular contribution of TLR9 and MyD88 signaling in individual DC subsets and evaluate the mechanism by which cDCs control MCMV immunity.

Original languageEnglish (US)
Pages (from-to)1113-1127
Number of pages15
JournalCell reports
Volume17
Issue number4
DOIs
StatePublished - Oct 18 2016

Bibliographical note

Funding Information:
We acknowledge Taconic Artemis for generating the TLR9 fl/fl mice in collaboration with H.W. and T.S. We thank Friederike Kruse for expert technical assistance and Lucía Minarrieta and Peyman Ghorbani for critical reading of the manuscript. In addition, we thank Dr. Till Strowig for the IFNAR-1 −/− mice and Dr. Tobias May for providing us with the Dox-MEF cell lines. We acknowledge the assistance of the Cell Sorting Core Facility of the Hannover Medical School, supported in part by Braukmann-Wittenberg-Herz-Stiftung and Deutsche Forschungsgemeinschaft. F.P. was supported by the HiLF foundation provided by the Hannover Medical School (MHH). M.F. was supported by the fellowship Ciências sem Fronteiras/DAAD. C.B. was supported by the European Molecular Biology Organization (EMBO). L.B. is supported by the Ellen-Schmidt Program from the MHH. Finally, we acknowledge the Deutsche Forschungsgemeinschaft SFB 900 (Sonderforschungsbereich 900) and the HiLF grant funding body for providing the financial resources to carry out this study.

Keywords

  • MCMV
  • NK cells
  • TLR9-MyD88 signaling
  • conventional DC
  • plasmacytoid DC

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