Neurotrophin Receptor p75NTR Regulates Immune Function of Plasmacytoid Dendritic Cells

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Abstract

Plasmacytoid dendritic cells (pDCs) regulate innate and adaptive immunity. Neurotrophins and their receptors control the function of neuronal tissue. In addition, they have been demonstrated to be part of the immune response but little is known about the effector immune cells involved. We report, for the first time, the expression and immune-regulatory function of the low affinity neurotrophin receptor p75 neurotrophin receptor (p75NTR) by the antigen-presenting pDCs, mediated by toll-like receptor (TLR) 9 activation and differential phosphorylation of interferon regulatory factor 3 and 7. The modulation of p75NTR on pDCs significantly influences disease progression of asthma in an ovalbumin-induced mouse model mediated by the TLR9 signaling pathway. p75NTR activation of pDCs from patients with asthma increased allergen-specific T cell proliferation and cytokine secretion in nerve growth factor concentration-dependent manner. Further, p75NTR activation of pDCs delayed the onset of autoimmune diabetes in RIP-CD80GP mice and aggravated graft-versus-host disease in a xenotransplantation model. Thus, p75NTR signaling on pDCs constitutes a new and critical mechanism connecting neurotrophin signaling and immune response regulation with great therapeutic potential for a variety of immune disorders.

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Most cited references 55

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T cell receptor antagonist peptides induce positive selection.

Kristin A. Hogquist, Stephen C. Jameson, William R. Heath … (1994)

We have used organ culture of fetal thymic lobes from T cell receptor (TCR) transgenic beta 2M(-/-) mice to study the role of peptides in positive selection. The TCR used was from a CD8+ T cell specific for ovalbumin 257-264 in the context of Kb. Several peptides with the ability to induce positive selection were identified. These peptide-selected thymocytes have the same phenotype as mature CD8+ T cells and can respond to antigen. Those peptides with the ability to induce positive selection were all variants of the antigenic peptide and were identified as TCR antagonist peptides for this receptor. One peptide tested, E1, induced positive selection on the beta 2M(-/-) background but negative selection on the beta 2M(+/-) background. These results show that the process of positive selection is exquisitely peptide specific and sensitive to extremely low ligand density and support the notion that low efficacy ligands mediate positive selection.

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Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements.

M. J. Barnden, J. Allison, W R Heath … (1998)

We describe the generation of ovalbumin (OVA)-specific, MHC class II-restricted alpha beta T cell receptor (TCR) transgenic mice. Initial attempts at generating these transgenic mice utilized heterologous regulatory elements to drive the expression of cDNA genes encoding the separate alpha- and beta-chains of the TCR. Unexpectedly, T cells bearing the transgenic alpha beta TCR failed to emerge from the thymus in these mice, although the transgenes did modify endogenous TCR expression. However, subsequent modification of the approach which enabled expression of the TCR beta-chain under the control of its natural regulatory elements generated mice whose peripheral T cells expressed the transgenic TCR and were capable of antigen-dependent proliferation. These results show that successful generation of MHC class II-restricted, OVA-specific alpha beta TCR transgenic mice was dependent upon combining cDNA- and genomic DNA-based constructs for expression of the respective alpha- and beta-chains of the TCR.

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Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6.

Taro Kawai, Shintaro Sato, Ken Ishii … (2004)

Toll-like receptors (TLRs) are involved in the recognition of microbial pathogens. A subset of TLRs, TLR7, TLR8 and TLR9, induces antiviral responses by producing interferon-alpha (IFN-alpha). Production of IFN-alpha is dependent on the Toll-interleukin-1 receptor domain-containing adaptor MyD88. Here we show that MyD88 formed a complex with the transcription factor IRF7 but not with IRF3. The death domain of MyD88 interacted with an inhibitory domain of IRF7, and this interaction resulted in activation of the IFN-alpha-dependent promoters. Furthermore, the adaptor molecule TRAF6 also bound and activated IRF7. Ubiquitin ligase activity of TRAF6 was required for IRF7 activation. These results indicate that TLR-mediated IFN-alpha induction requires the formation of a complex consisting of MyD88, TRAF6 and IRF7 as well as TRAF6-dependent ubiquitination.

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Author and article information

Contributors

Joanna Bandoła: URI : http://frontiersin.org/people/u/435117

Cornelia Richter: URI : http://frontiersin.org/people/u/31908

Arshad Jamal: URI : http://frontiersin.org/people/u/435893

Benjamin Dorschner: URI : http://frontiersin.org/people/u/436104

Ingo Roeder: URI : http://frontiersin.org/people/u/111053

Christian M. Hedrich: URI : http://frontiersin.org/people/u/69692

Sebastian Brenner: URI : http://frontiersin.org/people/u/442529

Sebastian Thieme: URI : http://frontiersin.org/people/u/436999

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immunol.

Title: Frontiers in Immunology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-3224

Publication date (Electronic): 17 August 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 981

Affiliations

[1] ¹Department of Pediatrics, University Clinic Dresden , Dresden, Germany

[2] ²Department of Medical Laboratory Sciences, Imperial College of Business Studies , Lahore, Pakistan

[3] ³DFG-Center for Regenerative Therapies Dresden, Cluster of Excellence, Technische Universitaet Dresden , Dresden, Germany

[4] ⁴Medical Clinic I, University Clinic Dresden , Dresden, Germany

[5] ⁵DKTK-German Cancer Consortium, Partner Site Dresden, University Clinic Dresden , Dresden, Germany

[6] ⁶DKFZ-German Cancer Research Center , Heidelberg, Germany

[7] ⁷Faculty of Medicine, Institute for Medical Informatics and Biometry, Technische Universitaet Dresden , Dresden, Germany

[8] ⁸BIOTEChnology Center/DFG-Center for Regenerative Therapies Dresden, Cluster of Excellence, Technische Universitaet Dresden , Dresden, Germany

Author notes

Edited by: Hubertus Hochrein, Bavarian Nordic, Germany

Reviewed by: Elodie Segura, Institut Curie, France; Cyril Seillet, Walter and Eliza Hall Institute of Medical Research, Australia

*Correspondence: Sebastian Brenner, sebastian.brenner@ 123456uniklinikum-dresden.de ; Sebastian Thieme, sebastian.thieme@ 123456uniklinikum-dresden.de

^†These authors have contributed equally to this work.

Specialty section: This article was submitted to Antigen Presenting Cell Biology, a section of the journal Frontiers in Immunology

Article

DOI: 10.3389/fimmu.2017.00981

PMC ID: 5562693

PubMed ID: 28861085

SO-VID: 3f8ee658-b91a-4724-a85d-3ba9110c83b5

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 28 April 2017

Date accepted : 31 July 2017

Page count

Figures: 5, Tables: 0, Equations: 0, References: 61, Pages: 16, Words: 11204

Funding

Funded by: Deutscher Akademischer Austauschdienst 10.13039/501100001655

Award ID: A/05/21256

Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659

Award ID: BR 2057/9-1, Sonderforschungsbereich 655

Funded by: Zentrum für Regenerative Therapien Dresden 10.13039/501100007491

Award ID: Seed grant

Funded by: Sächsisches Staatsministerium für Wissenschaft und Kunst 10.13039/501100006114

Neurotrophin Receptor p75NTR Regulates Immune Function of Plasmacytoid Dendritic Cells

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Gamma Delta T cells

Most cited references 55

T cell receptor antagonist peptides induce positive selection.

Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements.

Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6.

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