title: Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.
abstract: BACKGROUND
  DC are activated by pathogen-associated molecular patterns (PAMPs), and this is pivotal for the induction of adaptive immune responses. Thereafter, the clearance of activated DC is crucial to prevent immune pathology. While PAMPs are of major interest for vaccine science due to their adjuvant potential, it is unclear whether and how PAMPs may affect DC viability. We aimed to elucidate the possible apoptotic mechanisms that control activated DC lifespan in response to PAMPs, particularly in vivo.
  
  
  RESULTS
  We report that polyinosinic:polycytidylic acid (PolyIC, synthetic analogue of dsRNA) induces dramatic apoptosis of mouse splenic conventional DC (cDC) in vivo, predominantly affecting the CD8α subset, as shown by flow cytometry-based analysis of splenic DC subsets. Importantly, while Bim deficiency conferred only minor protection, cDC depletion was prevented in mice lacking Bim plus one of three other BH3-only proteins, either Puma, Noxa or Bid. Furthermore, we show that Type I Interferon (IFN) is necessary and sufficient for DC death both in vitro and in vivo, and that TLR3 and MAVS co-operate in IFNß production in vivo to induce DC death in response to PolyIC.
  
  
  CONCLUSIONS
  These results demonstrate for the first time in vivo that apoptosis restricts DC lifespan following activation by PolyIC, particularly affecting the CD8α cDC subset. Such DC apoptosis is mediated by the overlapping action of pro-apoptotic BH3-only proteins, including but not solely involving Bim, and is driven by Type I IFN. While Type I IFNs are important anti-viral factors, CD8α cDC are major cross-presenting cells and critical inducers of CTL. We discuss such paradoxical finding on DC death with PolyIC/Type I IFN. These results could contribute to understand immunosuppression associated with chronic infection, and to the optimization of DC-based therapies and the clinical use of PAMPs and Type I IFNs.
authors.affiliation: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: Silvia A
authors.initials: SA
authors.lastname: Fuertes Marraco
authors.forename: Clare L
authors.initials: CL
authors.lastname: Scott
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Annette
authors.initials: A
authors.lastname: Ives
authors.forename: Slavica
authors.initials: S
authors.lastname: Masina
authors.forename: David
authors.initials: D
authors.lastname: Vremec
authors.forename: Elisa S
authors.initials: ES
authors.lastname: Jansen
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: O'Reilly
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fasel
authors.forename: Ken
authors.initials: K
authors.lastname: Shortman
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Hans
authors.initials: H
authors.lastname: Acha-Orbea
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism; D002452:Cell Count; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007370:Interferon Type I / Q000096:biosynthesis / Q000494:pharmacology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000494:pharmacology; D007891:Leishmania / Q000502:physiology; D008024:Ligands; D008297:Male; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D016827:CD8 Antigens; D007370:Interferon Type I; D016899:Interferon-beta; D008024:Ligands; D011070:Poly I-C; D051196:Toll-Like Receptor 3; C409469:CD8 antigen, alpha chain; C512612:MAVS protein, mouse