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Journal of Virology, March 2003, p. 3799-3808, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3799-3808.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

T Cells Infiltrate the Brain in Murine and Human Transmissible Spongiform Encephalopathies{dagger}

Hanna Lewicki,1 Antoinette Tishon,1 Dirk Homann,1 Honoré Mazarguil,2 Françoise Laval,2 Valerie C. Asensio,3 Iain L. Campbell,3 Stephen DeArmond,4 Bryan Coon,1 Chao Teng,1 Jean Edouard Gairin,2 and Michael B. A. Oldstone1*

Division of Virology, Department of Neuropharmacology (IMM-6), The Scripps Research Institute, La Jolla, California 92037,1 Institut de Pharmacologie et de Biologie Structurale-UMR 5089, CNRS, 31077 Toulouse, Cedex 4, France,2 Department of Neuropharmacology (CVN-9),3 Department of Pathology, University of California—San Francisco, San Francisco, California 941434

Received 12 August 2002/ Accepted 26 November 2002

CD4 and CD8 T lymphocytes infiltrate the parenchyma of mouse brains several weeks after intracerebral, intraperitoneal, or oral inoculation with the Chandler strain of mouse scrapie, a pattern not seen with inoculation of prion protein knockout (PrP-/-) mice. Associated with this cellular infiltration are expression of MHC class I and II molecules and elevation in levels of the T-cell chemokines, especially macrophage inflammatory protein 1ß, IFN-{gamma}-inducible protein 10, and RANTES. T cells were also found in the central nervous system (CNS) in five of six patients with Creutzfeldt-Jakob disease. T cells harvested from brains and spleens of scrapie-infected mice were analyzed using a newly identified mouse PrP (mPrP) peptide bearing the canonical binding motifs to major histocompatibility complex (MHC) class I H-2b or H-2d molecules, appropriate MHC class I tetramers made to include these peptides, and CD4 and CD8 T cells stimulated with 15-mer overlapping peptides covering the whole mPrP. Minimal to modest Kb tetramer binding of mPrP amino acids (aa) 2 to 9, aa 152 to 160, and aa 232 to 241 was observed, but such tetramer-binding lymphocytes as well as CD4 and CD8 lymphocytes incubated with the full repertoire of mPrP peptides failed to synthesize intracellular gamma interferon (IFN-{gamma}) or tumor necrosis factor alpha (TNF-{alpha}) cytokines and were unable to lyse PrP-/- embryo fibroblasts or macrophages coated with 51Cr-labeled mPrP peptide. These results suggest that the expression of PrPsc in the CNS is associated with release of chemokines and, as shown previously, cytokines that attract and retain PrP-activated T cells and, quite likely, bystander activated T cells that have migrated from the periphery into the CNS. However, these CD4 and CD8 T cells are defective in such an effector function(s) as IFN-{gamma} and TNF-{alpha} expression or release or lytic activity.

* Corresponding author. Mailing address: Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8054. Fax: (858) 784-9981. E-mail: mbaobo{at}scripps.edu.

{dagger} This is publication number 13546-NP from the Department of Neuropharmacology, The Scripps Research Institute, La Jolla, Calif.

Journal of Virology, March 2003, p. 3799-3808, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3799-3808.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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