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Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling
Tumor progression in the host leads to severe impairment of intrathymic T-cell differentiation/maturation, leading to the paralysis of cellular anti-tumor immunity. Such suppression manifests the erosion of CD4(+)CD8(+) double-positive (DP) immature thymocytes and a gradual increase in CD4(−)CD8(−)...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292239/ https://www.ncbi.nlm.nih.gov/pubmed/32582141 http://dx.doi.org/10.3389/fimmu.2020.00898 |
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author | Guha, Ipsita Bhuniya, Avishek Shukla, Divanshu Patidar, Ashok Nandi, Partha Saha, Akata Dasgupta, Shayani Ganguly, Nilanjan Ghosh, Sweta Nair, Arathi Majumdar, Subrata Saha, Bhaskar Storkus, Walter J. Baral, Rathindranath Bose, Anamika |
author_facet | Guha, Ipsita Bhuniya, Avishek Shukla, Divanshu Patidar, Ashok Nandi, Partha Saha, Akata Dasgupta, Shayani Ganguly, Nilanjan Ghosh, Sweta Nair, Arathi Majumdar, Subrata Saha, Bhaskar Storkus, Walter J. Baral, Rathindranath Bose, Anamika |
author_sort | Guha, Ipsita |
collection | PubMed |
description | Tumor progression in the host leads to severe impairment of intrathymic T-cell differentiation/maturation, leading to the paralysis of cellular anti-tumor immunity. Such suppression manifests the erosion of CD4(+)CD8(+) double-positive (DP) immature thymocytes and a gradual increase in CD4(−)CD8(−) double negative (DN) early T-cell progenitors. The impact of such changes on the T-cell progenitor pool in the context of cancer remains poorly investigated. Here, we show that tumor progression blocks the transition of Lin(−)Thy1.2(+)CD25(+)CD44(+)c-Kit(low)DN2b to Lin(−)Thy1.2(+)CD25(+)CD44(−)c-Kit(−)DN3 in T-cell maturation, instead leading to DN2-T-cell differentiation into dendritic cells (DC). We observed that thymic IL-10 expression is upregulated, particularly at cortico-medullary junctions (CMJ), under conditions of progressive disease, resulting in the termination of IL-10R(high) DN2-T-cell maturation due to dysregulated expression of Notch1 and its target, CCR7 (thus restricting these cells to the CMJ). Intrathymic differentiation of T-cell precursors in IL-10(−/−) mice and in vitro fetal thymic organ cultures revealed that IL-10 promotes the interaction between thymic stromal cells and Notch1(low) DN2-T cells, thus facilitating these DN2-T cells to differentiate toward CD45(+)CD11c(+)MHC-II(+) thymic DCs as a consequence of activating the Ikaros/IRF8 signaling axis. We conclude that a novel function of thymically-expressed IL-10 in the tumor-bearing host diverts T-cell differentiation toward a DC pathway, thus limiting the protective adaptive immune repertoire. |
format | Online Article Text |
id | pubmed-7292239 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-72922392020-06-23 Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling Guha, Ipsita Bhuniya, Avishek Shukla, Divanshu Patidar, Ashok Nandi, Partha Saha, Akata Dasgupta, Shayani Ganguly, Nilanjan Ghosh, Sweta Nair, Arathi Majumdar, Subrata Saha, Bhaskar Storkus, Walter J. Baral, Rathindranath Bose, Anamika Front Immunol Immunology Tumor progression in the host leads to severe impairment of intrathymic T-cell differentiation/maturation, leading to the paralysis of cellular anti-tumor immunity. Such suppression manifests the erosion of CD4(+)CD8(+) double-positive (DP) immature thymocytes and a gradual increase in CD4(−)CD8(−) double negative (DN) early T-cell progenitors. The impact of such changes on the T-cell progenitor pool in the context of cancer remains poorly investigated. Here, we show that tumor progression blocks the transition of Lin(−)Thy1.2(+)CD25(+)CD44(+)c-Kit(low)DN2b to Lin(−)Thy1.2(+)CD25(+)CD44(−)c-Kit(−)DN3 in T-cell maturation, instead leading to DN2-T-cell differentiation into dendritic cells (DC). We observed that thymic IL-10 expression is upregulated, particularly at cortico-medullary junctions (CMJ), under conditions of progressive disease, resulting in the termination of IL-10R(high) DN2-T-cell maturation due to dysregulated expression of Notch1 and its target, CCR7 (thus restricting these cells to the CMJ). Intrathymic differentiation of T-cell precursors in IL-10(−/−) mice and in vitro fetal thymic organ cultures revealed that IL-10 promotes the interaction between thymic stromal cells and Notch1(low) DN2-T cells, thus facilitating these DN2-T cells to differentiate toward CD45(+)CD11c(+)MHC-II(+) thymic DCs as a consequence of activating the Ikaros/IRF8 signaling axis. We conclude that a novel function of thymically-expressed IL-10 in the tumor-bearing host diverts T-cell differentiation toward a DC pathway, thus limiting the protective adaptive immune repertoire. Frontiers Media S.A. 2020-06-05 /pmc/articles/PMC7292239/ /pubmed/32582141 http://dx.doi.org/10.3389/fimmu.2020.00898 Text en Copyright © 2020 Guha, Bhuniya, Shukla, Patidar, Nandi, Saha, Dasgupta, Ganguly, Ghosh, Nair, Majumdar, Saha, Storkus, Baral and Bose. http://creativecommons.org/licenses/by/4.0/ 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) and the copyright owner(s) 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. |
spellingShingle | Immunology Guha, Ipsita Bhuniya, Avishek Shukla, Divanshu Patidar, Ashok Nandi, Partha Saha, Akata Dasgupta, Shayani Ganguly, Nilanjan Ghosh, Sweta Nair, Arathi Majumdar, Subrata Saha, Bhaskar Storkus, Walter J. Baral, Rathindranath Bose, Anamika Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling |
title | Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling |
title_full | Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling |
title_fullStr | Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling |
title_full_unstemmed | Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling |
title_short | Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling |
title_sort | tumor arrests dn2 to dn3 pro t cell transition and promotes its conversion to thymic dendritic cells by reciprocally regulating notch1 and ikaros signaling |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292239/ https://www.ncbi.nlm.nih.gov/pubmed/32582141 http://dx.doi.org/10.3389/fimmu.2020.00898 |
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