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TOX is a critical regulator of tumour-specific T cell differentiation
Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states(1–6). Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed i...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698992/ https://www.ncbi.nlm.nih.gov/pubmed/31207604 http://dx.doi.org/10.1038/s41586-019-1324-y |
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author | Scott, Andrew C. Dündar, Friederike Zumbo, Paul Chandran, Smita S. Klebanoff, Christopher A. Shakiba, Mojdeh Trivedi, Prerak Menocal, Laura Appleby, Heather Camara, Steven Zamarin, Dmitriy Walther, tyler Snyder, Alexandra Femia, Matthew R. Comen, Elizabeth A. Wen, Hannah Y. Hellmann, Matthew D. Anandasabapathy, Niroshana Liu, Yong Altorki, Nasser K. Lauer, Peter Levy, Olivier Glickman, Michael S. Kaye, Jonathan Betel, Doron Philip, Mary Schietinger, Andrea |
author_facet | Scott, Andrew C. Dündar, Friederike Zumbo, Paul Chandran, Smita S. Klebanoff, Christopher A. Shakiba, Mojdeh Trivedi, Prerak Menocal, Laura Appleby, Heather Camara, Steven Zamarin, Dmitriy Walther, tyler Snyder, Alexandra Femia, Matthew R. Comen, Elizabeth A. Wen, Hannah Y. Hellmann, Matthew D. Anandasabapathy, Niroshana Liu, Yong Altorki, Nasser K. Lauer, Peter Levy, Olivier Glickman, Michael S. Kaye, Jonathan Betel, Doron Philip, Mary Schietinger, Andrea |
author_sort | Scott, Andrew C. |
collection | PubMed |
description | Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states(1–6). Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, ‘non-exhausted’ immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer. |
format | Online Article Text |
id | pubmed-7698992 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
record_format | MEDLINE/PubMed |
spelling | pubmed-76989922020-11-28 TOX is a critical regulator of tumour-specific T cell differentiation Scott, Andrew C. Dündar, Friederike Zumbo, Paul Chandran, Smita S. Klebanoff, Christopher A. Shakiba, Mojdeh Trivedi, Prerak Menocal, Laura Appleby, Heather Camara, Steven Zamarin, Dmitriy Walther, tyler Snyder, Alexandra Femia, Matthew R. Comen, Elizabeth A. Wen, Hannah Y. Hellmann, Matthew D. Anandasabapathy, Niroshana Liu, Yong Altorki, Nasser K. Lauer, Peter Levy, Olivier Glickman, Michael S. Kaye, Jonathan Betel, Doron Philip, Mary Schietinger, Andrea Nature Article Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states(1–6). Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, ‘non-exhausted’ immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer. 2019-06-17 2019-07 /pmc/articles/PMC7698992/ /pubmed/31207604 http://dx.doi.org/10.1038/s41586-019-1324-y Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Scott, Andrew C. Dündar, Friederike Zumbo, Paul Chandran, Smita S. Klebanoff, Christopher A. Shakiba, Mojdeh Trivedi, Prerak Menocal, Laura Appleby, Heather Camara, Steven Zamarin, Dmitriy Walther, tyler Snyder, Alexandra Femia, Matthew R. Comen, Elizabeth A. Wen, Hannah Y. Hellmann, Matthew D. Anandasabapathy, Niroshana Liu, Yong Altorki, Nasser K. Lauer, Peter Levy, Olivier Glickman, Michael S. Kaye, Jonathan Betel, Doron Philip, Mary Schietinger, Andrea TOX is a critical regulator of tumour-specific T cell differentiation |
title | TOX is a critical regulator of tumour-specific T cell differentiation |
title_full | TOX is a critical regulator of tumour-specific T cell differentiation |
title_fullStr | TOX is a critical regulator of tumour-specific T cell differentiation |
title_full_unstemmed | TOX is a critical regulator of tumour-specific T cell differentiation |
title_short | TOX is a critical regulator of tumour-specific T cell differentiation |
title_sort | tox is a critical regulator of tumour-specific t cell differentiation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698992/ https://www.ncbi.nlm.nih.gov/pubmed/31207604 http://dx.doi.org/10.1038/s41586-019-1324-y |
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