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Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation

Apoptosis is an important physiological process in development and disease. Apoptotic cells (ACs) are a major source of self-antigens, but ACs usually evade immune responses. The mechanism by which ACs repress T cell adaptive immune responses is poorly understood. T cell activation is finely regulat...

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Autores principales: Yakoub, Abraam M., Schulz, Ralph, Seiffert, Martina, Sadek, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043626/
https://www.ncbi.nlm.nih.gov/pubmed/30002409
http://dx.doi.org/10.1038/s41598-018-28901-0
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author Yakoub, Abraam M.
Schulz, Ralph
Seiffert, Martina
Sadek, Mark
author_facet Yakoub, Abraam M.
Schulz, Ralph
Seiffert, Martina
Sadek, Mark
author_sort Yakoub, Abraam M.
collection PubMed
description Apoptosis is an important physiological process in development and disease. Apoptotic cells (ACs) are a major source of self-antigens, but ACs usually evade immune responses. The mechanism by which ACs repress T cell adaptive immune responses is poorly understood. T cell activation is finely regulated by a balance of costimulatory signaling (mediated by the costimulatory receptor CD28 on T cells) and coinhibitory signaling (mediated by the coinhibitory ligands CD80 and PD-L1 and -2 on Antigen-Presenting Cells). Here, we found that ACs specifically upregulated the coinhibitory ligand CD80 on macrophages. Conversely, ACs did not exhibit a robust regulation of the other coinhibitory ligands on macrophages or the costimulatory receptor CD28 on T cells. We show that the robust positive regulation of CD80 by ACs requires phagocytosis of ACs by macrophages. We also demonstrate that CD80 modulation by dead cells is a specific effect of ACs, but not necrotic cells (which stimulate immune responses). These results indicate that ACs modulate the coinhibitory pathway of T cell activation via CD80, and suggest a role for CD80 in suppressing T cell responses by ACs. Understanding a mechanism of regulating adaptive immune responses to ACs, which harbor an abundance of self-antigens, may advance our understanding of mechanisms of regulating autoimmunity and facilitate future therapy development for autoimmune disorders.
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spelling pubmed-60436262018-07-15 Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation Yakoub, Abraam M. Schulz, Ralph Seiffert, Martina Sadek, Mark Sci Rep Article Apoptosis is an important physiological process in development and disease. Apoptotic cells (ACs) are a major source of self-antigens, but ACs usually evade immune responses. The mechanism by which ACs repress T cell adaptive immune responses is poorly understood. T cell activation is finely regulated by a balance of costimulatory signaling (mediated by the costimulatory receptor CD28 on T cells) and coinhibitory signaling (mediated by the coinhibitory ligands CD80 and PD-L1 and -2 on Antigen-Presenting Cells). Here, we found that ACs specifically upregulated the coinhibitory ligand CD80 on macrophages. Conversely, ACs did not exhibit a robust regulation of the other coinhibitory ligands on macrophages or the costimulatory receptor CD28 on T cells. We show that the robust positive regulation of CD80 by ACs requires phagocytosis of ACs by macrophages. We also demonstrate that CD80 modulation by dead cells is a specific effect of ACs, but not necrotic cells (which stimulate immune responses). These results indicate that ACs modulate the coinhibitory pathway of T cell activation via CD80, and suggest a role for CD80 in suppressing T cell responses by ACs. Understanding a mechanism of regulating adaptive immune responses to ACs, which harbor an abundance of self-antigens, may advance our understanding of mechanisms of regulating autoimmunity and facilitate future therapy development for autoimmune disorders. Nature Publishing Group UK 2018-07-12 /pmc/articles/PMC6043626/ /pubmed/30002409 http://dx.doi.org/10.1038/s41598-018-28901-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Yakoub, Abraam M.
Schulz, Ralph
Seiffert, Martina
Sadek, Mark
Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation
title Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation
title_full Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation
title_fullStr Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation
title_full_unstemmed Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation
title_short Autoantigen-Harboring Apoptotic Cells Hijack the Coinhibitory Pathway of T Cell Activation
title_sort autoantigen-harboring apoptotic cells hijack the coinhibitory pathway of t cell activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043626/
https://www.ncbi.nlm.nih.gov/pubmed/30002409
http://dx.doi.org/10.1038/s41598-018-28901-0
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