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...
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| Format: | Article |
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eLife Sciences Publications Ltd
2022-08-01
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| Online Access: | https://elifesciences.org/articles/76457 |
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| author | Karthik Chandiran Jenny E Suarez-Ramirez Yinghong Hu Evan R Jellison Zeynep Ugur Jun Siong Low Bryan McDonald Susan M Kaech Linda S Cauley |
| author_facet | Karthik Chandiran Jenny E Suarez-Ramirez Yinghong Hu Evan R Jellison Zeynep Ugur Jun Siong Low Bryan McDonald Susan M Kaech Linda S Cauley |
| author_sort | Karthik Chandiran |
| collection | DOAJ |
| 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, CX3CR1, 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. |
| first_indexed | 2024-04-11T10:45:21Z |
| format | Article |
| id | doaj.art-3e1aa3771a354027943ff186a8c20248 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:45:21Z |
| publishDate | 2022-08-01 |
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| record_format | Article |
| series | eLife |
| spelling | doaj.art-3e1aa3771a354027943ff186a8c202482022-12-22T04:29:05ZengeLife Sciences Publications LtdeLife2050-084X2022-08-011110.7554/eLife.76457SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLsKarthik Chandiran0https://orcid.org/0000-0003-2118-7946Jenny E Suarez-Ramirez1Yinghong Hu2Evan R Jellison3Zeynep Ugur4Jun Siong Low5Bryan McDonald6Susan M Kaech7Linda S Cauley8https://orcid.org/0000-0001-9488-0341Department of Immunology, University of Connecticut Health Center, Farmington, United StatesDepartment of Immunology, University of Connecticut Health Center, Farmington, United StatesDepartment of Microbiology and Immunology, Emory Vaccine Center, Emory University, Atlanta, United StatesDepartment of Immunology, University of Connecticut Health Center, Farmington, United StatesDepartment of Immunology, University of Connecticut Health Center, Farmington, United StatesDepartment of Immunobiology, Yale University School of Medicine, New Haven, United StatesNOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, United StatesNOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, United StatesDepartment of Immunology, University of Connecticut Health Center, Farmington, United StatesTransforming 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, CX3CR1, 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.https://elifesciences.org/articles/76457cytotoxic T lymphocyteSMAD4TGFβCD8 T cell differentiationCD8 memoryCD8 T cells |
| spellingShingle | Karthik Chandiran Jenny E Suarez-Ramirez Yinghong Hu Evan R Jellison Zeynep Ugur Jun Siong Low Bryan McDonald Susan M Kaech Linda S Cauley SMAD4 and TGFβ are architects of inverse genetic programs during fate determination of antiviral CTLs eLife cytotoxic T lymphocyte SMAD4 TGFβ CD8 T cell differentiation CD8 memory CD8 T cells |
| 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 | cytotoxic T lymphocyte SMAD4 TGFβ CD8 T cell differentiation CD8 memory CD8 T cells |
| url | https://elifesciences.org/articles/76457 |
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