Abstract

Lymphotoxin-α- and Lymphotoxin-β-Deficient Mice Differ in Susceptibility to Scrapie: Evidence against Dendritic Cell Involvement in Neuroinvasion † Michael B. A. Oldstone 1 , * , Richard Race 2 , Diane Thomas 1 , Hanna Lewicki 1 , Dirk Homann 1 , Sara Smelt 1 , Andreas Holz 1 , Pandelakis Koni 3 , David Lo 4 , Bruce Chesebro 2 , and Richard Flavell 3 1 Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037 2 Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Hamilton, Montana 59840 3 Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520 4 Digital Gene Technologies, Inc., La Jolla, California 92037 ABSTRACT Transmissible spongiform encephalopathy or prion diseases are fatal neurodegenerative disorders of humans and animals often initiated by oral intake of an infectious agent. Current evidence suggests that infection occurs initially in the lymphoid tissues and subsequently in the central nervous system (CNS). The identity of infected lymphoid cells remains controversial, but recent studies point to the involvement of both follicular dendritic cells (FDC) and CD11c + lymphoid dendritic cells. FDC generation and maintenance in germinal centers is dependent on lymphotoxin alpha (LT-α) and LT-β signaling components. We report here that by the oral route, LT-α −/− mice developed scrapie while LT-β −/− mice did not. Furthermore, LT-α −/− mice had a higher incidence and shorter incubation period for developing disease following inoculation than did LT-β −/− mice. Transplantation of lymphoid tissues from LT-β −/− mice, which have cervical and mesenteric lymph nodes, into LT-α −/− mice, which do not, did not alter the incidence of CNS scrapie. In other studies, a virus that is tropic for and alters functions of CD11c + cells did not alter the kinetics of neuroinvasion of scrapie. Our results suggest that neither FDC nor CD11c + cells are essential for neuroinvasion after high doses of RML scrapie. Further, it is possible that an as yet unidentified cell found more abundantly in LT-α −/− than in LT-β −/− mice may assist in the amplification of scrapie infection in the periphery and favor susceptibility to CNS disease following peripheral routes of infection.