Cell Reports

Volume 17, Issue 4, 18 October 2016, Pages 1113–1127

Open Access
Article

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

  • 1 Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research (Twincore), Hannover Medical School (MHH) and Helmholtz Centre for Infection Research (HZI), 30625 Hannover, Germany
  • 2 Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil
  • 3 Laboratorio de Virología, Departamento de Química Biológica, IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires C1428EGA, Argentina
  • 4 Department of Clinical Immunology and Rheumatology, MHH, 30625 Hannover, Germany
  • 5 Institute for Laboratory Animal Science, MHH, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
  • 6 Institute for Experimental Infection Research, Twincore, MHH and HZI, Feodor-Lynen-Strasse 7, 30625 Hannover, Germany
  • 7 Medical Department (Gastroenterology, Infectious Diseases and Rheumatology)/Research Center ImmunoScience, Charité–Universitätsmedizin Berlin, Campus Benjamin Franklin, 12200 Berlin, Germany
  • 8 Department for Vaccinology/Immune Aging and Chronic Infection, HZI, 38124 Braunschweig, Germany
  • 9 Department of Surgery, Technische Universität München, 81675 Munich, Germany
  • 10 Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, 81675 Munich, Germany
Received 26 June 2016, Revised 9 August 2016, Accepted 16 September 2016, Available online 18 October 2016
Published: October 18, 2016

Highlights

•

Generation of a mouse model to study DC-specific TLR9 function

•

cDC uses TLR9- and MyD88-dependent mechanisms to promote MCMV immunity

•

cDC-derived cytokines control independent NK cell effector responses against MCMV

Summary

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.

Graphical Abstract

Keywords

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

Introduction

Cytomegalovirus (CMV) exhibits a broad tropism in humans, leading to a diverse range of infection-associated pathologies (Tabeta et al., 2004). In immunocompromised people, such as AIDS and transplant patients, as well as in unborn individuals infected during gestation, CMV is highly pathogenic. Despite numerous efforts, no effective vaccine exists against CMV (Ahmed, 2011). Furthermore, current anti-viral therapy is associated with numerous drawbacks, such as poor bioavailability, development of anti-viral drug resistance, and associated cytotoxicities (Plotkin, 2015). This warrants for an urgent requirement to design alternative approaches to enhance immune responses against CMV.