TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function.
Natural interferon-producing cells (IPC) respond to viruses by secreting type I interferon (IFN) and interleukin-12 (IL-12). Toll-like receptor (TLR) 9 mediates IPC recognition of some of these viruses in vitro. However, whether TLR9-induced activation of IPC is necessary for an effective antiviral response in vivo is not clear. Here, we demonstrate that IPC and dendritic cells (DC) recognize murine cytomegalovirus (MCMV) through TLR9. TLR9-mediated cytokine secretion promotes viral clearance by NK cells that express the MCMV-specific receptor Ly49H. Although depletion of IPC leads to a drastic reduction of the IFN-alpha response, this allows other cell types to secrete IL-12, ensuring normal IFN-gamma and NK cell responses to MCMV. We conclude that the TLR9/MyD88 pathway mediates antiviral cytokine responses by IPC, DC, and possibly other cell types, which are coordinated to promote effective NK cell function and MCMV clearance.
Krug
Anne
A
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
French
Anthony R
AR
Barchet
Winfried
W
Fischer
Jens A A
JA
Dzionek
Andrzej
A
Pingel
Jeanette T
JT
Orihuela
Michael M
MM
Akira
Shizuo
S
Yokoyama
Wayne M
WM
Colonna
Marco
M
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology*; D007372:Interferons / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D051379:Mice; D018146:Muromegalovirus / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000502:physiology*; D011971:Receptors, Immunologic; D051217:Toll-Like Receptor 9; D014779:Virus Replication
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D004268:DNA-Binding Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D018664:Interleukin-12; D007372:Interferons