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      Natural Killer Cell Sensing of Infected Cells Compensates for MyD88 Deficiency but Not IFN-I Activity in Resistance to Mouse Cytomegalovirus

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          In mice, plasmacytoid dendritic cells (pDC) and natural killer (NK) cells both contribute to resistance to systemic infections with herpes viruses including mouse Cytomegalovirus (MCMV). pDCs are the major source of type I IFN (IFN-I) during MCMV infection. This response requires pDC-intrinsic MyD88-dependent signaling by Toll-Like Receptors 7 and 9. Provided that they express appropriate recognition receptors such as Ly49H, NK cells can directly sense and kill MCMV-infected cells. The loss of any one of these responses increases susceptibility to infection. However, the relative importance of these antiviral immune responses and how they are related remain unclear. In humans, while IFN-I responses are essential, MyD88 is dispensable for antiviral immunity. Hence, a higher redundancy has been proposed in the mechanisms promoting protective immune responses against systemic infections by herpes viruses during natural infections in humans. It has been assumed, but not proven, that mice fail to mount protective MyD88-independent IFN-I responses. In humans, the mechanism that compensates MyD88 deficiency has not been elucidated. To address these issues, we compared resistance to MCMV infection and immune responses between mouse strains deficient for MyD88, the IFN-I receptor and/or Ly49H. We show that selective depletion of pDC or genetic deficiencies for MyD88 or TLR9 drastically decreased production of IFN-I, but not the protective antiviral responses. Moreover, MyD88, but not IFN-I receptor, deficiency could largely be compensated by Ly49H-mediated antiviral NK cell responses. Thus, contrary to the current dogma but consistent with the situation in humans, we conclude that, in mice, in our experimental settings, MyD88 is redundant for IFN-I responses and overall defense against a systemic herpes virus infection. Moreover, we identified direct NK cell sensing of infected cells as one mechanism able to compensate for MyD88 deficiency in mice. Similar mechanisms likely contribute to protect MyD88- or IRAK4-deficient patients from viral infections.

          Author Summary

          Type I interferons (IFN-I) are innate cytokines crucial for vertebrate antiviral defenses. IFN-I exert antiviral effector functions and orchestrate antiviral immunity. IFN-I are induced early after infection, upon sensing of viral particles or infected cells by immune receptors. Intracellular Toll-like receptors (TLR) are selectively expressed in specialized immune cell types such as plasmacytoid dendritic cells (pDC), enabling them to copiously produce IFN-I upon detection of engulfed viral nucleic acids. pDC or intracellular TLR have been reported to be crucial for resistance to experimental infections with many viruses in mice but dispensable for resistance to natural infections in humans. Our aim was to investigate this puzzling difference. Mice deficient for TLR activity mounted strong IFN-I responses despite producing very low IFN-I levels and controlled the infection by a moderate dose of murine cytomegalovirus much better than mice deficient for IFN-I responses. Deficient TLR responses could be compensated by direct recognition of infected cells by natural killer cells. Hence, we identified experimental conditions in mice mimicking the lack of requirement of TLR functions for antiviral defense observed in humans. We used these experimental models to advance our basic understanding of antiviral immunity in a way that might help improve treatments for patients.

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          Most cited references 80

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          Functional role of type I and type II interferons in antiviral defense.

          Mice lacking the known subunit of the type I interferon (IFN) receptor were completely unresponsive to type I IFNs, suggesting that this receptor chain is essential for type I IFN-mediated signal transduction. These mice showed no overt anomalies but were unable to cope with viral infections, despite otherwise normal immune responses. Comparison of mice lacking either type I or type II IFN receptors showed that, at least in response to some viruses, both IFN systems are essential for antiviral defense and are functionally nonredundant.
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            The interleukin-1 family: back to the future.

            Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes seven ligands with agonist activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) family include six receptor chains forming four signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP), and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors, and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 family members. Moreover, IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity. Copyright © 2013 Elsevier Inc. All rights reserved.
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              T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses.

              The pathogen recognition theory dictates that, upon viral infection, the innate immune system first detects microbial products and then responds by providing instructions to adaptive CD8 T cells. Here, we show in mice that tissue resident memory CD8 T cells (T(RM) cells), non-recirculating cells located at common sites of infection, can achieve near-sterilizing immunity against viral infections by reversing this flow of information. Upon antigen resensitization within the mouse female reproductive mucosae, CD8(+) T(RM) cells secrete cytokines that trigger rapid adaptive and innate immune responses, including local humoral responses, maturation of local dendritic cells, and activation of natural killer cells. This provided near-sterilizing immunity against an antigenically unrelated viral infection. Thus, CD8(+) T(RM) cells rapidly trigger an antiviral state by amplifying receptor-derived signals from previously encountered pathogens. Copyright © 2014, American Association for the Advancement of Science.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                8 May 2015
                May 2015
                : 11
                : 5
                [1 ]Centre d’Immunologie de Marseille-Luminy, UNIV UM2, Aix Marseille Université, Parc Scientifique et Technologique de Luminy, Marseille, France
                [2 ]Institut National de la Santé et de la Recherche Médicale (INSERM), U1104, Marseille, France
                [3 ]Centre National de la Recherche Scientifique (CNRS), UMR7280, Marseille, France
                University of California, San Francisco, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CC RG MD. Performed the experiments: CC RG GB LC MB MD. Analyzed the data: CC RG MD. Contributed reagents/materials/analysis tools: LC KC. Wrote the paper: CC MD.


                Current Address: Laboratoire Génétique, Reproduction et Développement, Clermont Université, CNRS UMR 6293, INSERM U1103, Aubière, France


                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Figures: 5, Tables: 0, Pages: 23
                This research was funded by grants from Agence Nationale de la Recherche (ANR)(EMICIF, reference ANR-08-MIEN-008-02) and from Fondation pour la Recherche Médicale (FRM, reference DEQ20110421284), as well as by institutional support from CNRS, Inserm and Aix-Marseille Université. We also acknowledge support from the DCBIOL Labex (ANR-11-LABEX-0043, grant ANR-10-IDEX-0001-02 PSL*) and the A*MIDEX project (ANR-11-IDEX-0001-02) funded by the French Government's “Investissements d'Avenir” program managed by the ANR. CC was supported by the FRM and by the DCBIOL Labex. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
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                All relevant data are within the paper and its Supporting Information files, except for microarray data which is available from the GEO database (accession number GSE62729).

                Infectious disease & Microbiology


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