title: Friend retrovirus drives cytotoxic effectors through Toll-like receptor 3.
abstract: BACKGROUND
  Pathogen recognition drives host defense towards viral infections. Specific groups rather than single members of the protein family of pattern recognition receptors (PRRs) such as membrane spanning Toll-like receptors (TLRs) and cytosolic helicases might mediate sensing of replication intermediates of a specific virus species. TLR7 mediates host sensing of retroviruses and could significantly influence retrovirus-specific antibody responses. However, the origin of efficient cell-mediated immunity towards retroviruses is unknown. Double-stranded RNA intermediates produced during retroviral replication are good candidates for immune stimulatory viral products. Thus, we considered TLR3 as primer of cell-mediated immunity against retroviruses in vivo.
  
  
  RESULTS
  Infection of mice deficient in TLR3 (TLR3(-/-)) with Friend retrovirus (FV) complex revealed higher viral loads during acute retroviral infection compared to wild type mice. TLR3(-/-) mice exhibited significantly lower expression levels of type I interferons (IFNs) and IFN-stimulated genes like Pkr or Ifi44, as well as reduced numbers of activated myeloid dendritic cells (DCs) (CD86(+) and MHC-II(+)). DCs generated from FV-infected TLR3(-/-) mice were less capable of priming virus-specific CD8(+) T cell proliferation. Moreover, cytotoxicity of natural killer (NK) cells as well as CD8(+) T cells were reduced in vitro and in vivo, respectively, in FV-infected TLR3(-/-) mice.
  
  
  CONCLUSIONS
  TLR3 mediates antiretroviral cytotoxic NK cell and CD8(+) T cell activity in vivo. Our findings qualify TLR3 as target of immune therapy against retroviral infections.
authors.affiliation: Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany. Kathrin.Gibbert@uni-due.de.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gibbert
authors.affiliation: Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany. Sandra.Francois@uk-essen.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Francois
authors.affiliation: Institute for Medical Microbiology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany. Anna.Sigmund@uk-essen.de.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Sigmund
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO, 80045, USA. Michael.Harper@ucdenver.com.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Harper
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO, 80045, USA. Brad.Barrett@ucdenver.com.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Barrett
authors.affiliation: Institute for Medical Microbiology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany. Carsten.Kirschning@uk-essen.de.
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirchning
authors.affiliation: Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany. Mengji.Lu@uni-due.de.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO, 80045, USA. Mario.Santiago@ucdenver.com.
authors.forename: Mario L
authors.initials: ML
authors.lastname: Santiago
authors.affiliation: Institute for Virology of the University Hospital in Essen, University of Duisburg-Essen, Essen, Germany. Ulf.Dittmer@uni-due.de.
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005622:Friend murine leukemia virus / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D007942:Leukemia, Experimental / Q000276:immunology / Q000821:virology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012192:Retroviridae Infections / Q000276:immunology / Q000821:virology; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000276:immunology / Q000821:virology; D019562:Viral Load
chemical_list: D051196:Toll-Like Receptor 3