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Release and Initiation of Immune Responses In Vivo1
* Schering-Plough, Laboratory for Immunological Research, Dardilly, France;
Centre d’Immunologie de Marseille-Luminy, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de la Méditerranée, Marseille, France;
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique-INSERM-Universit é Louis Pasteur, Illkirch, France;
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and
¶ Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912
Antiviral immunity requires early and late mechanisms in which IFN-
and IL-12 play major roles. However, the initial events leading to their production remain largely unclear. Given the crucial role of TLR in innate recognition, we investigated their role in antiviral immunity in vivo. Upon murine CMV (MCMV) infection, both MyD88–/– and TLR9–/– mice were more susceptible and presented increased viral loads compared with C57BL/6, TLR2–/–, TLR3–/–, or TLR4–/– mice. However, in terms of resistance to infection, IFN- production and in many other parameters of early inflammatory responses, the MyD88–/– mice showed a more defective response than TLR9–/– mice. In the absence of the TLR9/MyD88 signaling pathway, cytokine production was dramatically impaired with a complete abolition of bioactive IL-12p70 serum release contrasting with a high flexibility for IFN- release, which is initially (36 h) plasmacytoid dendritic cell- and MyD88-dependent, and subsequently (44 h) PDC-, MyD88-independent and, most likely, TLR-independent. NK cells from MCMV-infected MyD88–/– and TLR9–/– mice displayed a severely impaired IFN-
production, yet retained enhanced cytotoxic activity. In addition, dendritic cell activation and critical inflammatory cell trafficking toward the liver were still effective. In the long term, except for isotype switching to MCMV-specific IgG1, the establishment of Ab responses was not significantly altered. Thus, our results demonstrate a critical requirement of TLR9 in the process of MCMV sensing to assure rapid antiviral responses, coordinated with other TLR-dependent and -independent events that are sufficient to establish adaptive immunity.
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