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Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα(+) Dendritic Cells: A Murine Model

Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-...

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Autores principales: Baba, Tomohisa, Badr, Mohamed El Sherif, Tomaru, Utano, Ishizu, Akihiro, Mukaida, Naofumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397991/
https://www.ncbi.nlm.nih.gov/pubmed/22815949
http://dx.doi.org/10.1371/journal.pone.0041154
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author Baba, Tomohisa
Badr, Mohamed El Sherif
Tomaru, Utano
Ishizu, Akihiro
Mukaida, Naofumi
author_facet Baba, Tomohisa
Badr, Mohamed El Sherif
Tomaru, Utano
Ishizu, Akihiro
Mukaida, Naofumi
author_sort Baba, Tomohisa
collection PubMed
description Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-specific antigen may have contradictory roles in tumor immunity in a context-dependent manner. However, it remains elusive on the precise cellular mechanism of intrathymic immune tolerance against tumor antigens. We previously demonstrated that a minor thymic conventional dendritic cell (cDC) subset, CD8α(−)Sirpα(+) cDCs, but not the major subset, CD8α(+)Sirpα(−) cDCs can selectively capture blood-borne antigens and crucially contribute to the self-tolerance. In the present study, we further demonstrated that Sirpα(+) cDCs can capture a blood-borne antigen leaking inside the interlobular vascular-rich regions (IVRs). Blood-borne antigen selectively captured by Sirpα(+) cDCs can induce antigen-specific Treg generation or negative selection, depending on the immunogenicity of the presented antigen. Furthermore, CCR2 expression by thymic Sirpα(+) cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirpα(+) cDCs in tumor-bearing mice. Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. Moreover, tumor formation induced the accumulation of Sirpα(+) cDCs in IVRs under the control of CCR2-CCL2 axis and enhanced their capacity to take up antigens, resulting in the shift from Treg differentiation to negative selection. Finally, intrathymic negative selection similarly ensued in CCR2-competent mice once the tumor-specific antigen was secreted into bloodstream. Thus, we demonstrated that thymic Sirpα(+) cDCs crucially contribute to this novel process of intrathymic tumor immune tolerance.
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spelling pubmed-33979912012-07-19 Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα(+) Dendritic Cells: A Murine Model Baba, Tomohisa Badr, Mohamed El Sherif Tomaru, Utano Ishizu, Akihiro Mukaida, Naofumi PLoS One Research Article Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-specific antigen may have contradictory roles in tumor immunity in a context-dependent manner. However, it remains elusive on the precise cellular mechanism of intrathymic immune tolerance against tumor antigens. We previously demonstrated that a minor thymic conventional dendritic cell (cDC) subset, CD8α(−)Sirpα(+) cDCs, but not the major subset, CD8α(+)Sirpα(−) cDCs can selectively capture blood-borne antigens and crucially contribute to the self-tolerance. In the present study, we further demonstrated that Sirpα(+) cDCs can capture a blood-borne antigen leaking inside the interlobular vascular-rich regions (IVRs). Blood-borne antigen selectively captured by Sirpα(+) cDCs can induce antigen-specific Treg generation or negative selection, depending on the immunogenicity of the presented antigen. Furthermore, CCR2 expression by thymic Sirpα(+) cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirpα(+) cDCs in tumor-bearing mice. Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. Moreover, tumor formation induced the accumulation of Sirpα(+) cDCs in IVRs under the control of CCR2-CCL2 axis and enhanced their capacity to take up antigens, resulting in the shift from Treg differentiation to negative selection. Finally, intrathymic negative selection similarly ensued in CCR2-competent mice once the tumor-specific antigen was secreted into bloodstream. Thus, we demonstrated that thymic Sirpα(+) cDCs crucially contribute to this novel process of intrathymic tumor immune tolerance. Public Library of Science 2012-07-16 /pmc/articles/PMC3397991/ /pubmed/22815949 http://dx.doi.org/10.1371/journal.pone.0041154 Text en Baba et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Baba, Tomohisa
Badr, Mohamed El Sherif
Tomaru, Utano
Ishizu, Akihiro
Mukaida, Naofumi
Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα(+) Dendritic Cells: A Murine Model
title Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα(+) Dendritic Cells: A Murine Model
title_full Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα(+) Dendritic Cells: A Murine Model
title_fullStr Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα(+) Dendritic Cells: A Murine Model
title_full_unstemmed Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα(+) Dendritic Cells: A Murine Model
title_short Novel Process of Intrathymic Tumor-Immune Tolerance through CCR2-Mediated Recruitment of Sirpα(+) Dendritic Cells: A Murine Model
title_sort novel process of intrathymic tumor-immune tolerance through ccr2-mediated recruitment of sirpα(+) dendritic cells: a murine model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397991/
https://www.ncbi.nlm.nih.gov/pubmed/22815949
http://dx.doi.org/10.1371/journal.pone.0041154
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