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

PLoS Pathog. 2015 May 8;11(5):e1004897. doi: 10.1371/journal.ppat.1004897. eCollection 2015 May.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / virology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Herpesviridae Infections / blood
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / metabolism
  • Herpesviridae Infections / virology
  • Host-Pathogen Interactions*
  • Immunity, Innate
  • Immunologic Deficiency Syndromes / immunology
  • Immunologic Deficiency Syndromes / metabolism
  • Immunologic Deficiency Syndromes / virology
  • Interferon Type I / blood
  • Interferon Type I / metabolism*
  • Interleukin-12 / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / virology
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Mutant Strains
  • Muromegalovirus / immunology*
  • Muromegalovirus / physiology
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / metabolism*
  • NK Cell Lectin-Like Receptor Subfamily A / deficiency
  • NK Cell Lectin-Like Receptor Subfamily A / genetics
  • NK Cell Lectin-Like Receptor Subfamily A / metabolism
  • Primary Immunodeficiency Diseases
  • Receptor, Interferon alpha-beta / agonists*
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism
  • Signal Transduction
  • Specific Pathogen-Free Organisms
  • Spleen / immunology
  • Spleen / metabolism
  • Spleen / virology
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / metabolism

Substances

  • Ifnar1 protein, mouse
  • Interferon Type I
  • Klra8 protein, mouse
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NK Cell Lectin-Like Receptor Subfamily A
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Receptor, Interferon alpha-beta
  • Interleukin-12

Supplementary concepts

  • MYD88 Deficiency

Associated data

  • GEO/GSE62729

Grants and funding

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.