Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion

Abstract

Peripheral infection is the natural route of transmission in most prion diseases1. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion2 and progressive neurological disease. Both immune cells and nerves are involved in pathogenesis3,4, but the mechanisms of prion transfer from the immune to the nervous system are unknown. Here we show that ablation of the chemokine receptor CXCR5 juxtaposes follicular dendritic cells (FDCs) to major splenic nerves, and accelerates the transfer of intraperitoneally administered prions into the spinal cord. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves: transfer of CXCR5-/- bone marrow to wild-type mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to CXCR5-/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signalling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in CXCR5-/- mice. This suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.

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Figure 1: Neuroimmune anatomy of CXCR5-/- and WT mice.
Figure 2: Kinetics of prion disease in CXCR5-/- and WT mice.
Figure 3: Splenic prion replication in CXCR5-/- mice in the absence of LTβR signalling.
Figure 4: FDC localization and prion replication in LTβR-Fc treated mice and bone-marrow chimaeras.

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Acknowledgements

We thank C. Sigurdson and M. Zabel for critical reading of the manuscript, and R. Zinkernagel for support. This work was supported by grants of the Bundesamt für Bildung und Wissenschaft, the Swiss National Foundation, the NCCR on neural plasticity and repair, and the Migros foundation to A.A. M.P. was a postdoctoral fellow of the Deutsche Forschungsgemeinschaft. M.H. is supported by a generous educational grant of the Catello family and by the Verein zur Förderung des Akademischen Nachwuchses. F.L.H. is supported by the Stammbach Foundation and by the Bonizzi-Theler Foundation.

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Correspondence to Adriano Aguzzi.

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Prinz, M., Heikenwalder, M., Junt, T. et al. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425, 957–962 (2003) doi:10.1038/nature02072

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