SMAD4 and TGFβ are architects of inverse genetic programs during fate-determination of antiviral CTLs
- University of Connecticut Health Center, United States
- Emory University, United States
- Yale University, Switzerland
- Salk Institute for Biological Studies, United States
Abstract
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-programing 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. TGFb uses a canonical SMAD-dependent signaling pathway to down-regulate 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 shows that signaling via SMAD4 promotes formation of terminally-differentiated CTLs that localize in the vasculature. Our data shows 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.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE151637Figure 3-source data 1 contain the numerical data used to generate the figures
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Transcriptional profile of SMAD4-deficient cells is similar to TRMNCBI Gene Expression Omnibus, GSE151637.
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Molecular signature of brain resident memory CD8+ T cellsNCBI Gene Expression Omnibus, GSE39152.
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RNA-Seq of CD8+ T cell subsets during LCMV infectionNCBI Gene Expression Omnibus, GSE107281.
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Hobit and Blimp1 instruct a universal transcriptional program of tissue-residency in lymphocytesNCBI Gene Expression Omnibus, GSE70813.
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SMAD4 CHip-seqNCBI Gene Expression Omnibus, GSE135533.
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (R01 AI123864)
- Susan M Kaech
- Linda S Cauley
American association for Immunologists (AAI Careers in Immunology Fellowship)
- Linda S Cauley
University of Connecticut Health Center (bridge funding)
- Linda S Cauley
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Urszula Krzych, Walter Reed Army Institute of Research, United States
Ethics
Animal experimentation: Experiments were performed in accordance with protocol AP-200531-0824 approved by the UCONN Health Institutional Animal Care and Use Committee (IACUC). Every effort was made to minimize suffering.
Version history
- Preprint posted: December 16, 2021 (view preprint)
- Received: December 17, 2021
- Accepted: August 5, 2022
- Accepted Manuscript published: August 9, 2022 (version 1)
- Accepted Manuscript updated: August 11, 2022 (version 2)
- Version of Record published: August 24, 2022 (version 3)
- Version of Record updated: August 30, 2022 (version 4)
Copyright
© 2022, Chandiran et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SMAD4 and TGFβ are architects of inverse genetic programs during fate-determination of antiviral CTLs
eLife 11:e76457.
https://doi.org/10.7554/eLife.76457
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