Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells

The immune system is central in the pathogenesis of scrapie and other trans missible spongiform encephalopathies (TSEs) or 'prion' diseases(1). After i nfecting by peripheral (intraperitoneal or oral) routes, most TSE agents re plicate in spleen and lymph nodes before neuroinvasion(2). Characterization of the cells supporting replication in these tissues is essential to under standing early pathogenesis and may indicate potential targets for therapy, for example, in 'new variant' Creutzfeldt-Jakob disease. The host 'prion' protein (PrP) is required for TSE agent replication(3,4) and accumulates in modified forms in infected tissues. Abnormal PrP is detected readily on fo llicular dendritic cells (FDCs) in lymphoid tissues of patients with 'new v ariant' Creutzfeldt-Jakob disease(5), sheep with natural scrapie(6) and mic e experimentally infected with scrapie(7). The normal protein is present on FDCs in uninfected mice(7) and, at lower levels, on lymphocytes(8). Studie s using severe combined immunodeficiency (SCID) mice, with and without bone marrow (BM) grafts, have indicated involvement of FDCs and/or lymphocytes in scrapie pathogenesis(9). To clarify the separate roles of FDCs and lymph ocytes, we produced chimeric mice with a mismatch in PrP status between FDC s and other cells of the immune system, by grafting bone marrow from PrP-de ficient knockout mice(4) into PrP-expressing mice and vice versa. Using the se chimeric models, we obtained strong evidence that FDCs themselves produc e PrP and that replication of a mouse-passaged scrapie strain in spleen dep ends on PrP-expressing FDCs rather than on lymphocytes or other bone marrow -derived cells.