Lymphotoxin, but Not TNF, Is Required for Prion Invasion of Lymph Nodes

PLoS Pathogens

Jana Sponarova¹  Tracy O'Connor¹  Mathias Heikenwalder¹  Adriano Aguzzi¹  Nathalie Frei¹  Petra Schwarz¹ 

[1] Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland

关键词: Lymph nodes;    Spleen;    Animal prion diseases;    Cytokines;    Prion diseases;    Immunohistochemistry techniques;    Macrophages;    Immunofluorescence;   

DOI  :  10.1371/journal.ppat.1002867

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 PrPSc detection, we identified PrPSc 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.

【 授权许可】

CC BY