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Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells
While inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Journal Experts
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202434/ https://www.ncbi.nlm.nih.gov/pubmed/34127967 http://dx.doi.org/10.21203/rs.3.rs-133494/v1 |
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author | Hafler, David Sumida, Tomokazu Dulberg, Shai Schupp, Jonas Stillwell, Helen Axisa, Pierre-Paul Comi, Michela Lincoln, Matthew Unterman, Avraham Kaminski, Naftali Madi, Asaf Kuchroo, Vijay |
author_facet | Hafler, David Sumida, Tomokazu Dulberg, Shai Schupp, Jonas Stillwell, Helen Axisa, Pierre-Paul Comi, Michela Lincoln, Matthew Unterman, Avraham Kaminski, Naftali Madi, Asaf Kuchroo, Vijay |
author_sort | Hafler, David |
collection | PubMed |
description | While inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of T cell exhaustion in chronic viral infection. Here we show that IFN-I regulates co-inhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while surprisingly inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses enabled the construction of dynamic transcriptional regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors on human primary T cells revealed unique regulators that control expression of co-inhibitory receptors. We found that the dynamic IFN-I response in vitro closely mirrored T cell features with IFN-I linked acute SARS-CoV-2 infection in human, with high LAG3 and decreased TIGIT expression. Finally, our gene regulatory network identified SP140 as a key regulator for differential LAG3 and TIGIT expression, which were validated at the level of protein expression. The construction of IFN-I regulatory networks with identification of unique transcription factors controlling co-inhibitory receptor expression may provide targets for enhancement of immunotherapy in cancer, infectious diseases, and autoimmunity. |
format | Online Article Text |
id | pubmed-8202434 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Journal Experts |
record_format | MEDLINE/PubMed |
spelling | pubmed-82024342021-06-15 Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells Hafler, David Sumida, Tomokazu Dulberg, Shai Schupp, Jonas Stillwell, Helen Axisa, Pierre-Paul Comi, Michela Lincoln, Matthew Unterman, Avraham Kaminski, Naftali Madi, Asaf Kuchroo, Vijay Res Sq Article While inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of T cell exhaustion in chronic viral infection. Here we show that IFN-I regulates co-inhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while surprisingly inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses enabled the construction of dynamic transcriptional regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors on human primary T cells revealed unique regulators that control expression of co-inhibitory receptors. We found that the dynamic IFN-I response in vitro closely mirrored T cell features with IFN-I linked acute SARS-CoV-2 infection in human, with high LAG3 and decreased TIGIT expression. Finally, our gene regulatory network identified SP140 as a key regulator for differential LAG3 and TIGIT expression, which were validated at the level of protein expression. The construction of IFN-I regulatory networks with identification of unique transcription factors controlling co-inhibitory receptor expression may provide targets for enhancement of immunotherapy in cancer, infectious diseases, and autoimmunity. American Journal Experts 2021-06-08 /pmc/articles/PMC8202434/ /pubmed/34127967 http://dx.doi.org/10.21203/rs.3.rs-133494/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. https://creativecommons.org/licenses/by/4.0/License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License (https://creativecommons.org/licenses/by/4.0/) |
spellingShingle | Article Hafler, David Sumida, Tomokazu Dulberg, Shai Schupp, Jonas Stillwell, Helen Axisa, Pierre-Paul Comi, Michela Lincoln, Matthew Unterman, Avraham Kaminski, Naftali Madi, Asaf Kuchroo, Vijay Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells |
title | Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells |
title_full | Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells |
title_fullStr | Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells |
title_full_unstemmed | Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells |
title_short | Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in Human T cells |
title_sort | type i interferon transcriptional network regulates expression of coinhibitory receptors in human t cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202434/ https://www.ncbi.nlm.nih.gov/pubmed/34127967 http://dx.doi.org/10.21203/rs.3.rs-133494/v1 |
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