Abstract
Neuroinvasion and subsequent destruction of the central nervous system by prions are typically preceded by a colonization phase in lymphoid organs. An important compartment harboring prions in lymphoid tissue is the follicular dendritic cell (FDC), which requires both tumor necrosis factor receptor 1 (TNFR1) and lymphotoxin β receptor (LTβR) signaling for maintenance. However, prions are still detected in TNFR1⁻/⁻ lymph nodes despite the absence of mature FDCs. Here we show that TNFR1-independent prion accumulation in lymph nodes depends on LTβR signaling. Loss of LTβR signaling, but not of TNFR1, was concurrent with the dedifferentiation of high endothelial venules (HEVs) required for lymphocyte entry into lymph nodes. Using luminescent conjugated polymers for histochemical PrP(Sc) detection, we identified PrP(Sc) deposits associated with HEVs in TNFR1⁻/⁻ lymph nodes. Hence, prions may enter lymph nodes by HEVs and accumulate or replicate in the absence of mature FDCs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Dendritic Cells, Follicular / immunology*
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Dendritic Cells, Follicular / metabolism
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Dendritic Cells, Follicular / pathology
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Lymph Nodes / immunology*
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Lymph Nodes / metabolism
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Lymph Nodes / pathology
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Lymphotoxin beta Receptor / genetics
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Lymphotoxin beta Receptor / immunology
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Lymphotoxin beta Receptor / metabolism
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Lymphotoxin-alpha / genetics
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Lymphotoxin-alpha / immunology*
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Lymphotoxin-alpha / metabolism
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Mice
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Mice, Knockout
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PrPSc Proteins / genetics
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PrPSc Proteins / immunology*
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PrPSc Proteins / metabolism
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / immunology
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Scrapie / genetics
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Scrapie / immunology*
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Scrapie / metabolism
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Scrapie / pathology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Ltbr protein, mouse
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Lymphotoxin beta Receptor
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Lymphotoxin-alpha
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PrPSc Proteins
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Receptors, Tumor Necrosis Factor, Type I
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Tnfrsf1a protein, mouse
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Tumor Necrosis Factor-alpha
Grants and funding
A.A. is the recipient of a European Research Council Advanced Investigator Award. M.H. is a recipient of a European Research Council Starting Investigator Award. T.O. is supported by a fellowship from the University of Zürich. J.S. is supported by a FEBS long-term fellowship. This work was funded by Swiss National Science Foundation grant # 3100A0-111917 to A.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.