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
-
Transcriptional profile of SMAD4-deficient cells is similar to TRMNCBI Gene Expression Omnibus, GSE151637.
-
Molecular signature of brain resident memory CD8+ T cellsNCBI Gene Expression Omnibus, GSE39152.
-
RNA-Seq of CD8+ T cell subsets during LCMV infectionNCBI Gene Expression Omnibus, GSE107281.
-
Hobit and Blimp1 instruct a universal transcriptional program of tissue-residency in lymphocytesNCBI Gene Expression Omnibus, GSE70813.
-
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.
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.
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.
Metrics
-
- 1,102
- views
-
- 263
- downloads
-
- 7
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Innate immune responses triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection play pivotal roles in the pathogenesis of COVID-19, while host factors including proinflammatory cytokines are critical for viral containment. By utilizing quantitative and qualitative models, we discovered that soluble factors secreted by human monocytes potently inhibit SARS-CoV-2-induced cell-cell fusion in viral-infected cells. Through cytokine screening, we identified that interleukin-1β (IL-1β), a key mediator of inflammation, inhibits syncytia formation mediated by various SARS-CoV-2 strains. Mechanistically, IL-1β activates RhoA/ROCK signaling through a non-canonical IL-1 receptor-dependent pathway, which drives the enrichment of actin bundles at the cell-cell junctions, thus prevents syncytia formation. Notably, in vivo infection experiments in mice confirmed that IL-1β significantly restricted SARS-CoV-2 spread in the lung epithelium. Together, by revealing the function and underlying mechanism of IL-1β on SARS-CoV-2-induced cell-cell fusion, our study highlights an unprecedented antiviral function for cytokines during viral infection.
-
- Immunology and Inflammation
Gout is a prevalent form of inflammatory arthritis that occurs due to high levels of uric acid in the blood leading to the formation of urate crystals in and around the joints, particularly affecting the elderly. Recent research has provided evidence of distinct differences in the gut microbiota of patients with gout and hyperuricemia compared to healthy individuals. However, the link between gut microbiota and age-related gout remained underexplored. Our study found that gut microbiota plays a crucial role in determining susceptibility to age-related gout. Specifically, we observed that age-related gut microbiota regulated the activation of the NLRP3 inflammasome pathway and modulated uric acid metabolism. More scrutiny highlighted the positive impact of ‘younger’ microbiota on the gut microbiota structure of old or aged mice, enhancing butanoate metabolism and butyric acid content. Experimentation with butyrate supplementation indicated that butyric acid exerts a dual effect, inhibiting inflammation in acute gout and reducing serum uric acid levels. These insights emphasize the potential of gut microbiome rejuvenation in mitigating senile gout, unraveling the intricate dynamics between microbiota, aging, and gout. It potentially serves as a therapeutic target for senile gout-related conditions.
