Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling

Research output: Contribution to journalArticle

Wei Hu, Stefan Nessler, Bernhard Hemmer, Todd N. Eagar, Lawrence P. Kane, S. Rutger Leliveld, Andreas Müller-Schiffmann, Anne R. Gocke, Amy Lovett-Racke, Li Hong Ben, Rehana Z. Hussain, Andreas Breil, Jeffrey L. Elliott, Krishna Puttaparthi, Petra D. Cravens, Mahendra P. Singh, Benjamin Petsch, Lothar Stitz, Michael K. Racke, Carsten Korth & 1 others Olaf Stüve

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 protein1-11 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.

Original languageEnglish (US)
Pages (from-to)375-388
Number of pages14
JournalBrain
Volume133
Issue number2
DOIs
StatePublished - Feb 1 2010

PMID: 20145049

PMCID: PMC2822628

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Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling. / Hu, Wei; Nessler, Stefan; Hemmer, Bernhard; Eagar, Todd N.; Kane, Lawrence P.; Leliveld, S. Rutger; Müller-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; Stüve, Olaf.

In: Brain, Vol. 133, No. 2, 01.02.2010, p. 375-388.

Research output: Contribution to journalArticle

Harvard

Hu, W, Nessler, S, Hemmer, B, Eagar, TN, Kane, LP, Leliveld, SR, Müller-Schiffmann, A, Gocke, AR, Lovett-Racke, A, Ben, LH, Hussain, RZ, Breil, A, Elliott, JL, Puttaparthi, K, Cravens, PD, Singh, MP, Petsch, B, Stitz, L, Racke, MK, Korth, C & Stüve, O 2010, 'Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling' Brain, vol. 133, no. 2, pp. 375-388. https://doi.org/10.1093/brain/awp298

APA

Hu, W., Nessler, S., Hemmer, B., Eagar, T. N., Kane, L. P., Leliveld, S. R., ... Stüve, O. (2010). Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling. Brain, 133(2), 375-388. https://doi.org/10.1093/brain/awp298

Vancouver

Hu W, Nessler S, Hemmer B, Eagar TN, Kane LP, Leliveld SR et al. Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling. Brain. 2010 Feb 1;133(2):375-388. https://doi.org/10.1093/brain/awp298

Author

Hu, Wei ; Nessler, Stefan ; Hemmer, Bernhard ; Eagar, Todd N. ; Kane, Lawrence P. ; Leliveld, S. Rutger ; Müller-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 ; Stüve, Olaf. / Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling. In: Brain. 2010 ; Vol. 133, No. 2. pp. 375-388.

BibTeX

@article{90d46553e6f0481b8964ca3c4fd1ed3c,
title = "Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling",
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 protein1-11 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.",
keywords = "Immunosuppression, Prion, Small interfering RNA, T cell signaling",
author = "Wei Hu and Stefan Nessler and Bernhard Hemmer and Eagar, {Todd N.} and Kane, {Lawrence P.} and Leliveld, {S. Rutger} and Andreas M{\"u}ller-Schiffmann and Gocke, {Anne R.} and Amy Lovett-Racke and Ben, {Li Hong} and Hussain, {Rehana Z.} and Andreas Breil and Elliott, {Jeffrey L.} and Krishna Puttaparthi and Cravens, {Petra D.} and Singh, {Mahendra P.} and Benjamin Petsch and Lothar Stitz and Racke, {Michael K.} and Carsten Korth and Olaf St{\"u}ve",
year = "2010",
month = "2",
day = "1",
doi = "10.1093/brain/awp298",
language = "English (US)",
volume = "133",
pages = "375--388",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "2",

}

RIS

TY - JOUR

T1 - Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling

AU - Hu, Wei

AU - Nessler, Stefan

AU - Hemmer, Bernhard

AU - Eagar, Todd N.

AU - Kane, Lawrence P.

AU - Leliveld, S. Rutger

AU - Müller-Schiffmann, Andreas

AU - Gocke, Anne R.

AU - Lovett-Racke, Amy

AU - Ben, Li Hong

AU - Hussain, Rehana Z.

AU - Breil, Andreas

AU - Elliott, Jeffrey L.

AU - Puttaparthi, Krishna

AU - Cravens, Petra D.

AU - Singh, Mahendra P.

AU - Petsch, Benjamin

AU - Stitz, Lothar

AU - Racke, Michael K.

AU - Korth, Carsten

AU - Stüve, Olaf

PY - 2010/2/1

Y1 - 2010/2/1

N2 - 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 protein1-11 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.

AB - 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 protein1-11 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.

KW - Immunosuppression

KW - Prion

KW - Small interfering RNA

KW - T cell signaling

UR - http://www.scopus.com/inward/record.url?scp=77249104004&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77249104004&partnerID=8YFLogxK

U2 - 10.1093/brain/awp298

DO - 10.1093/brain/awp298

M3 - Article

VL - 133

SP - 375

EP - 388

JO - Brain

T2 - Brain

JF - Brain

SN - 0006-8950

IS - 2

ER -

ID: 16800760