Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling
2010 | journal article. A publication with affiliation to the University of Göttingen.
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Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling
Hu, W.; Nessler, S.; Hemmer, B.; Eagar, T. N.; Kane, L. P.; Leliveld, S. R. & Mueller-Schiffmann, A. et al. (2010)
Brain, 133 pp. 375-388. DOI: https://doi.org/10.1093/brain/awp298
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Details
- Authors
- Hu, Wei; Nessler, Stefan; Hemmer, Bernhard; Eagar, Todd N.; Kane, Lawrence P.; Leliveld, S. Rutger; Mueller-Schiffmann, Andreas; Gocke, Anne R.; Lovett-Racke, Amy; Ben, Li-Hong; Hussain, Rehana Z.; Breil, Andreas; Elliott, Jeffrey L.; Puttaparthi, Krishna; Cravens, Petra D.; Singh, Mahendra P.; Petsch, Benjamin; Stitz, Lothar; Racke, Michael K.; Korth, Carsten; Stuve, Olaf
- Abstract
- The primary biological function of the endogenous cellular prion protein has remained unclear. We investigated its biological function in the generation of cellular immune responses using cellular prion protein gene-specific small interfering ribonucleic acid in vivo and in vitro. Our results were confirmed by blocking cellular prion protein with monovalent antibodies and by using cellular prion protein-deficient and -transgenic mice. In vivo prion protein gene-small interfering ribonucleic acid treatment effects were of limited duration, restricted to secondary lymphoid organs and resulted in a 70% reduction of cellular prion protein expression in leukocytes. Disruption of cellular prion protein signalling augmented antigen-specific activation and proliferation, and enhanced T cell receptor signalling, resulting in zeta-chain-associated protein-70 phosphorylation and nuclear factor of activated T cells/activator protein 1 transcriptional activity. In vivo prion protein gene-small interfering ribonucleic acid treatment promoted T cell differentiation towards pro-inflammatory phenotypes and increased survival of antigen-specific T cells. Cellular prion protein silencing with small interfering ribonucleic acid also resulted in the worsening of actively induced and adoptively transferred experimental autoimmune encephalomyelitis. Finally, treatment of myelin basic protein(1-11) T cell receptor transgenic mice with prion protein gene-small interfering ribonucleic acid resulted in spontaneous experimental autoimmune encephalomyelitis. Thus, central nervous system autoimmune disease was modulated at all stages of disease: the generation of the T cell effector response, the elicitation of T effector function and the perpetuation of cellular immune responses. Our findings indicate that cellular prion protein regulates T cell receptor-mediated T cell activation, differentiation and survival. Defects in autoimmunity are restricted to the immune system and not the central nervous system. Our data identify cellular prion protein as a regulator of cellular immunological homoeostasis and suggest cellular prion protein as a novel potential target for therapeutic immunomodulation.
- Issue Date
- 2010
- Status
- published
- Publisher
- Oxford Univ Press
- Journal
- Brain
- ISSN
- 0006-8950