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An autonomous TCR signal-sensing switch influences CD4/CD8 lineage choice in mice
How multipotential cells initiate distinct gene expression programs in response to external cues to instruct cell fate choice remains a fundamental question in biology. Establishment of CD4 and CD8 T cell fates during thymocyte development is critically regulated by T cell receptor (TCR) signals, wh...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783009/ https://www.ncbi.nlm.nih.gov/pubmed/35064205 http://dx.doi.org/10.1038/s42003-022-02999-5 |
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author | Basu, Jayati Zha, Jikun Nicolas, Emmanuelle Coulton, Michael Czyzewicz, Philip Hua, Xiang Ge, Lu Kappes, Dietmar J. |
author_facet | Basu, Jayati Zha, Jikun Nicolas, Emmanuelle Coulton, Michael Czyzewicz, Philip Hua, Xiang Ge, Lu Kappes, Dietmar J. |
author_sort | Basu, Jayati |
collection | PubMed |
description | How multipotential cells initiate distinct gene expression programs in response to external cues to instruct cell fate choice remains a fundamental question in biology. Establishment of CD4 and CD8 T cell fates during thymocyte development is critically regulated by T cell receptor (TCR) signals, which in turn control expression of the CD4-determining transcription factor ThPOK. However, the mechanism whereby differential TCR signals are molecularly interpreted to promote or antagonize ThPOK expression, and thereby CD4 versus CD8 lineage fates remains unknown. Here we show, using reverse genetic and molecular approaches that an autonomous, position-independent TCR-sensing switch is embedded within the ThPOK locus. Further, using an in vivo mutagenesis approach, we demonstrate that differential TCR signals are interpreted during lineage commitment by relative binding of EGR, NFAT and Ebox factors to this bistable switch. Collectively our study reveals the central molecular mechanism whereby TCR signaling influences differential lineage choice. Ultimately, these findings may provide an important new tool for skewing T cell fate to treat cancer and autoimmune diseases. |
format | Online Article Text |
id | pubmed-8783009 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-87830092022-02-04 An autonomous TCR signal-sensing switch influences CD4/CD8 lineage choice in mice Basu, Jayati Zha, Jikun Nicolas, Emmanuelle Coulton, Michael Czyzewicz, Philip Hua, Xiang Ge, Lu Kappes, Dietmar J. Commun Biol Article How multipotential cells initiate distinct gene expression programs in response to external cues to instruct cell fate choice remains a fundamental question in biology. Establishment of CD4 and CD8 T cell fates during thymocyte development is critically regulated by T cell receptor (TCR) signals, which in turn control expression of the CD4-determining transcription factor ThPOK. However, the mechanism whereby differential TCR signals are molecularly interpreted to promote or antagonize ThPOK expression, and thereby CD4 versus CD8 lineage fates remains unknown. Here we show, using reverse genetic and molecular approaches that an autonomous, position-independent TCR-sensing switch is embedded within the ThPOK locus. Further, using an in vivo mutagenesis approach, we demonstrate that differential TCR signals are interpreted during lineage commitment by relative binding of EGR, NFAT and Ebox factors to this bistable switch. Collectively our study reveals the central molecular mechanism whereby TCR signaling influences differential lineage choice. Ultimately, these findings may provide an important new tool for skewing T cell fate to treat cancer and autoimmune diseases. Nature Publishing Group UK 2022-01-21 /pmc/articles/PMC8783009/ /pubmed/35064205 http://dx.doi.org/10.1038/s42003-022-02999-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Basu, Jayati Zha, Jikun Nicolas, Emmanuelle Coulton, Michael Czyzewicz, Philip Hua, Xiang Ge, Lu Kappes, Dietmar J. An autonomous TCR signal-sensing switch influences CD4/CD8 lineage choice in mice |
title | An autonomous TCR signal-sensing switch influences CD4/CD8 lineage choice in mice |
title_full | An autonomous TCR signal-sensing switch influences CD4/CD8 lineage choice in mice |
title_fullStr | An autonomous TCR signal-sensing switch influences CD4/CD8 lineage choice in mice |
title_full_unstemmed | An autonomous TCR signal-sensing switch influences CD4/CD8 lineage choice in mice |
title_short | An autonomous TCR signal-sensing switch influences CD4/CD8 lineage choice in mice |
title_sort | autonomous tcr signal-sensing switch influences cd4/cd8 lineage choice in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783009/ https://www.ncbi.nlm.nih.gov/pubmed/35064205 http://dx.doi.org/10.1038/s42003-022-02999-5 |
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