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In Vivo Depletion of CD11c⁺ Cells Impairs Scrapie Agent Neuroinvasion from the Intestine¹

Claudine R. Raymond^*, Pierre Aucouturier and Neil A. Mabbott^2,*

^* Roslin Institute Neuropathogenesis Unit and Royal (Dick) School of Veterinary Sciences, Edinburgh, United Kingdom; and Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S712, Hôpital St.-Antoine and Université Pierre et Marie Curie-Paris 6, Paris, France

Following oral exposure, some transmissible spongiform encephalopathy (TSE) agents accumulate first upon follicular dendritic cells (DCs) in the GALT. Studies in mice have shown that TSE agent accumulation in the GALT, in particular the Peyer’s patches, is obligatory for the efficient transmission of disease to the brain. However, the mechanism through which TSE agents are initially conveyed from the gut lumen to the GALT is not known. Studies have implicated migratory hemopoietic DCs in this process, but direct demonstration of their involvement in vivo is lacking. In this study, we have investigated the contribution of CD11c⁺ DCs in scrapie agent neuroinvasion through use of CD11c-diptheria toxin receptor-transgenic mice in which CD11c⁺ DCs can be specifically and transiently depleted. Using two distinct scrapie agent strains (ME7 and 139A scrapie agents), we show that when CD11c⁺ DCs were transiently depleted in the GALT and spleen before oral exposure, early agent accumulation in these tissues was blocked. In addition, CD11c⁺ cell depletion reduced susceptibility to oral scrapie challenge indicating that TSE agent neuroinvasion from the GALT was impaired. In conclusion, these data demonstrate that migratory CD11c⁺ DCs play a key role in the translocation of the scrapie agent from the gut lumen to the GALT from which neuroinvasion subsequently occurs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funding from the European Commission (Grant QLK5-CT-2002-1044) and the U.K. Biotechnology and Biological Sciences Research Council.

² Address correspondence and reprint requests to Dr. Neil A. Mabbott, Neuropathogenesis Unit, Roslin Institute, Ogston Building, West Mains Road, Edinburgh EH9 3JF, U.K. E-mail address: neil.mabbott{at}bbsrc.ac.uk

³ Abbreviations used in this paper: TSE, transmissible spongiform encephalopathy; PrP, prion protein; FAE, follicle-associated epithelium; DC, dendritic cell; FDC, follicular DC; PP, Peyer’s patch; MLN, mesenteric lymph node; DTR, diphtheria toxin receptor; tg, transgenic; DTX, diphtheria toxin; WT, wild type; i.c., intracerebral; GFAP, glial fibrillary acid protein; pAb, polyclonal Ab.

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The JI 2007 179: 7191-7192. [Full Text]