Lymphocytoid choriomeningitis virus activates plasmacytoid dendritic cells and induces a cytotoxic T-cell response via MyD88.
Toll-like receptors (TLRs) and retinoic acid-inducible gene I-like helicases (RLHs) are two major machineries recognizing RNA virus infection of innate immune cells. Intracellular signaling for TLRs and RLHs is mediated by their cytoplasmic adaptors, i.e., MyD88 or TRIF and IPS-1, respectively. In the present study, we investigated the contributions of TLRs and RLHs to the cytotoxic T-lymphocyte (CTL) response by using lymphocytoid choriomeningitis virus (LCMV) as a model virus. The generation of virus-specific cytotoxic T lymphocytes was critically dependent on MyD88 but not on IPS-1. Type I interferons (IFNs) are known to be important for the development of the CTL response to LCMV infection. Serum levels of type I IFNs and proinflammatory cytokines were mainly dependent on the presence of MyD88, although IPS-1(-/-) mice showed a decrease in IFN-alpha levels but not in IFN-beta and proinflammatory cytokine levels. Analysis of Ifna6(+/GFP) reporter mice revealed that plasmacytoid dendritic cells (DCs) are the major source of IFN-alpha in LCMV infection. MyD88(-/-) mice were highly susceptible to LCMV infection in vivo. These results suggest that recognition of LCMV by plasmacytoid DCs via TLRs is responsible for the production of type I IFNs in vivo. Furthermore, the activation of a MyD88-dependent innate mechanism induces a CTL response, which eventually leads to virus elimination.
Jung
Andreas
A
WPI Immunology Frontier Research Center, Laboratory of Host Defense, Osaka University, 3-1 Yamada-oka, Suita 565-0871, Osaka, Japan.
Kato
Hiroki
H
Kumagai
Yutaro
Y
Kumar
Himanshu
H
Kawai
Taro
T
Takeuchi
Osamu
O
Akira
Shizuo
S
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000276:immunology; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology*; D004198:Disease Susceptibility / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; C512612:MAVS protein, mouse; C507780:Myd88 protein, mouse