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Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance
Thymic central tolerance is a critical process that prevents autoimmunity but also presents a challenge to the generation of anti-tumor immune responses. Medullary thymic epithelial cells (mTECs) eliminate self-reactive T cells by displaying a diverse repertoire of tissue-specific antigens (TSAs) th...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010907/ https://www.ncbi.nlm.nih.gov/pubmed/24752296 http://dx.doi.org/10.1084/jem.20131889 |
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author | Khan, Imran S. Mouchess, Maria L. Zhu, Meng-Lei Conley, Bridget Fasano, Kayla J. Hou, Yafei Fong, Lawrence Su, Maureen A. Anderson, Mark S. |
author_facet | Khan, Imran S. Mouchess, Maria L. Zhu, Meng-Lei Conley, Bridget Fasano, Kayla J. Hou, Yafei Fong, Lawrence Su, Maureen A. Anderson, Mark S. |
author_sort | Khan, Imran S. |
collection | PubMed |
description | Thymic central tolerance is a critical process that prevents autoimmunity but also presents a challenge to the generation of anti-tumor immune responses. Medullary thymic epithelial cells (mTECs) eliminate self-reactive T cells by displaying a diverse repertoire of tissue-specific antigens (TSAs) that are also shared by tumors. Therefore, while protecting against autoimmunity, mTECs simultaneously limit the generation of tumor-specific effector T cells by expressing tumor self-antigens. This ectopic expression of TSAs largely depends on autoimmune regulator (Aire), which is expressed in mature mTECs. Thus, therapies to deplete Aire-expressing mTECs represent an attractive strategy to increase the pool of tumor-specific effector T cells. Recent work has implicated the TNF family members RANK and RANK-Ligand (RANKL) in the development of Aire-expressing mTECs. We show that in vivo RANKL blockade selectively and transiently depletes Aire and TSA expression in the thymus to create a window of defective negative selection. Furthermore, we demonstrate that RANKL blockade can rescue melanoma-specific T cells from thymic deletion and that persistence of these tumor-specific effector T cells promoted increased host survival in response to tumor challenge. These results indicate that modulating central tolerance through RANKL can alter thymic output and potentially provide therapeutic benefit by enhancing anti-tumor immunity. |
format | Online Article Text |
id | pubmed-4010907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-40109072014-11-05 Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance Khan, Imran S. Mouchess, Maria L. Zhu, Meng-Lei Conley, Bridget Fasano, Kayla J. Hou, Yafei Fong, Lawrence Su, Maureen A. Anderson, Mark S. J Exp Med Brief Definitive Report Thymic central tolerance is a critical process that prevents autoimmunity but also presents a challenge to the generation of anti-tumor immune responses. Medullary thymic epithelial cells (mTECs) eliminate self-reactive T cells by displaying a diverse repertoire of tissue-specific antigens (TSAs) that are also shared by tumors. Therefore, while protecting against autoimmunity, mTECs simultaneously limit the generation of tumor-specific effector T cells by expressing tumor self-antigens. This ectopic expression of TSAs largely depends on autoimmune regulator (Aire), which is expressed in mature mTECs. Thus, therapies to deplete Aire-expressing mTECs represent an attractive strategy to increase the pool of tumor-specific effector T cells. Recent work has implicated the TNF family members RANK and RANK-Ligand (RANKL) in the development of Aire-expressing mTECs. We show that in vivo RANKL blockade selectively and transiently depletes Aire and TSA expression in the thymus to create a window of defective negative selection. Furthermore, we demonstrate that RANKL blockade can rescue melanoma-specific T cells from thymic deletion and that persistence of these tumor-specific effector T cells promoted increased host survival in response to tumor challenge. These results indicate that modulating central tolerance through RANKL can alter thymic output and potentially provide therapeutic benefit by enhancing anti-tumor immunity. The Rockefeller University Press 2014-05-05 /pmc/articles/PMC4010907/ /pubmed/24752296 http://dx.doi.org/10.1084/jem.20131889 Text en © 2014 Khan et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Brief Definitive Report Khan, Imran S. Mouchess, Maria L. Zhu, Meng-Lei Conley, Bridget Fasano, Kayla J. Hou, Yafei Fong, Lawrence Su, Maureen A. Anderson, Mark S. Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance |
title | Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance |
title_full | Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance |
title_fullStr | Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance |
title_full_unstemmed | Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance |
title_short | Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance |
title_sort | enhancement of an anti-tumor immune response by transient blockade of central t cell tolerance |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010907/ https://www.ncbi.nlm.nih.gov/pubmed/24752296 http://dx.doi.org/10.1084/jem.20131889 |
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