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SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs
Transforming growth factor β (TGFβ) is an important differentiation factor for cytotoxic T lymphocytes (CTLs) and alters the expression levels of several of homing receptors during infection. SMAD4 is part of the canonical signaling network used by members of the transforming growth factor family. F...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402230/ https://www.ncbi.nlm.nih.gov/pubmed/35942952 http://dx.doi.org/10.7554/eLife.76457 |
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author | Chandiran, Karthik Suarez-Ramirez, Jenny E Hu, Yinghong Jellison, Evan R Ugur, Zeynep Low, Jun Siong McDonald, Bryan Kaech, Susan M Cauley, Linda S |
author_facet | Chandiran, Karthik Suarez-Ramirez, Jenny E Hu, Yinghong Jellison, Evan R Ugur, Zeynep Low, Jun Siong McDonald, Bryan Kaech, Susan M Cauley, Linda S |
author_sort | Chandiran, Karthik |
collection | PubMed |
description | Transforming growth factor β (TGFβ) is an important differentiation factor for cytotoxic T lymphocytes (CTLs) and alters the expression levels of several of homing receptors during infection. SMAD4 is part of the canonical signaling network used by members of the transforming growth factor family. For this study, genetically modified mice were used to determine how SMAD4 and TGFβ receptor II (TGFβRII) participate in transcriptional programming of pathogen-specific CTLs. We show that these molecules are essential components of opposing signaling mechanisms, and cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissues. TGFβ uses a canonical SMAD-dependent signaling pathway to downregulate Eomesodermin (EOMES), KLRG1, and CD62L, while CD103 is induced. Conversely, in vivo and in vitro data show that EOMES, KLRG1, CX(3)CR1, and CD62L are positively regulated via SMAD4, while CD103 and Hobit are downregulated. Intravascular staining also shows that signaling via SMAD4 promotes formation of long-lived terminally differentiated CTLs that localize in the vasculature. Our data show that inflammatory molecules play a key role in lineage determination of pathogen-specific CTLs, and use SMAD-dependent signaling to alter the expression levels of multiple homing receptors and transcription factors with known functions during memory formation. |
format | Online Article Text |
id | pubmed-9402230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-94022302022-08-25 SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs Chandiran, Karthik Suarez-Ramirez, Jenny E Hu, Yinghong Jellison, Evan R Ugur, Zeynep Low, Jun Siong McDonald, Bryan Kaech, Susan M Cauley, Linda S eLife Immunology and Inflammation Transforming growth factor β (TGFβ) is an important differentiation factor for cytotoxic T lymphocytes (CTLs) and alters the expression levels of several of homing receptors during infection. SMAD4 is part of the canonical signaling network used by members of the transforming growth factor family. For this study, genetically modified mice were used to determine how SMAD4 and TGFβ receptor II (TGFβRII) participate in transcriptional programming of pathogen-specific CTLs. We show that these molecules are essential components of opposing signaling mechanisms, and cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissues. TGFβ uses a canonical SMAD-dependent signaling pathway to downregulate Eomesodermin (EOMES), KLRG1, and CD62L, while CD103 is induced. Conversely, in vivo and in vitro data show that EOMES, KLRG1, CX(3)CR1, and CD62L are positively regulated via SMAD4, while CD103 and Hobit are downregulated. Intravascular staining also shows that signaling via SMAD4 promotes formation of long-lived terminally differentiated CTLs that localize in the vasculature. Our data show that inflammatory molecules play a key role in lineage determination of pathogen-specific CTLs, and use SMAD-dependent signaling to alter the expression levels of multiple homing receptors and transcription factors with known functions during memory formation. eLife Sciences Publications, Ltd 2022-08-09 /pmc/articles/PMC9402230/ /pubmed/35942952 http://dx.doi.org/10.7554/eLife.76457 Text en © 2022, Chandiran et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Immunology and Inflammation Chandiran, Karthik Suarez-Ramirez, Jenny E Hu, Yinghong Jellison, Evan R Ugur, Zeynep Low, Jun Siong McDonald, Bryan Kaech, Susan M Cauley, Linda S SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs |
title | SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs |
title_full | SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs |
title_fullStr | SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs |
title_full_unstemmed | SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs |
title_short | SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs |
title_sort | smad4 and tgfβ are architects of inverse genetic programs during fate determination of antiviral ctls |
topic | Immunology and Inflammation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402230/ https://www.ncbi.nlm.nih.gov/pubmed/35942952 http://dx.doi.org/10.7554/eLife.76457 |
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