title: Plasmacytoid dendritic cells sequester high prion titres at early stages of prion infection.
abstract: In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with a release of exosome-like membrane vesicles.
authors.affiliation: MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
authors.forename: Rocio
authors.initials: R
authors.lastname: Castro-Seoane
authors.forename: Holger
authors.initials: H
authors.lastname: Hummerich
authors.forename: Trevor
authors.initials: T
authors.lastname: Sweeting
authors.forename: M Howard
authors.initials: MH
authors.lastname: Tattum
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Linehan
authors.forename: Mar
authors.initials: M
authors.lastname: Fernandez de Marco
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Peter-Christian
authors.initials: PC
authors.lastname: Klöhn
mesh_terms: D000818:Animals; D002469:Cell Separation; D003713:Dendritic Cells / Q000378:metabolism / Q000648:ultrastructure*; D055354:Exosomes / Q000378:metabolism / Q000648:ultrastructure*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D018621:PrPC Proteins / Q000032:analysis* / Q000378:metabolism / Q000648:ultrastructure; D012608:Scrapie / Q000378:metabolism / Q000473:pathology*; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D018621:PrPC Proteins