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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
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.
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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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