Abstract
Pattern recognition by Toll-like receptors (TLRs) is known to be important for the induction of dendritic cell (DC) maturation. DCs, in turn, are critically important in the initiation of T cell responses. However, most viruses do not infect DCs. This recognition system poses a biological problem in ensuring that most viral infections be detected by pattern recognition receptors. Furthermore, it is unknown what, if any, is the contribution of TLRs expressed by cells that are infected by a virus, versus TLRs expressed by DCs, in the initiation of antiviral adaptive immunity. Here we address these issues using a physiologically relevant model of mucosal infection with herpes simplex virus type 2. We demonstrate that innate immune recognition of viral infection occurs in two distinct stages, one at the level of the infected epithelial cells and the other at the level of the noninfected DCs. Importantly, both TLR-mediated recognition events are required for the induction of effector T cells. Our results demonstrate that virally infected tissues instruct DCs to initiate the appropriate class of effector T cell responses and reveal the critical importance of the stromal cells in detecting infectious agents through their own pattern recognition receptors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / physiology
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Caspase 1 / deficiency
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Caspase 1 / genetics
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Cell Differentiation
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Cell Movement
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / virology*
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Female
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Herpesvirus 2, Human / immunology
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Herpesvirus 2, Human / pathogenicity
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Immunity, Innate
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Interferon gamma Receptor
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Interleukin-12 / deficiency
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Interleukin-12 / genetics
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / physiology*
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Receptors, Immunologic / deficiency
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology
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Receptors, Interferon / deficiency
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Receptors, Interferon / genetics
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Signal Transduction
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Stromal Cells / immunology
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Stromal Cells / virology
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Th1 Cells / immunology
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Toll-Like Receptors
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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MYD88 protein, human
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Cell Surface
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Receptors, Immunologic
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Receptors, Interferon
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Toll-Like Receptors
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Interleukin-12
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Caspase 1