TCR Transgenic Mice Reveal Stepwise, Multi-site Acquisition of the Distinctive Fat-Treg Phenotype
Open accessAbstract
Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario. Genesis of the VAT-Treg phenotype entailed a priming step in the spleen, permitting them to exit the lymphoid organs and surveil nonlymphoid tissues, and a final diversification process within VAT, in response to microenvironmental cues. Understanding the principles of tissue-Treg biology is a prerequisite for precision-targeting strategies.
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Tissue Treg cell precursor development is initiated in lymphatic organs and follows a multistep model.
“Tissue Treg cell precursor development is initiated in lymphatic organs and, thereby, follows a multistep model [375, 377, 452, 453].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [452]
The Abstract and Discussion (pages not provided) describe a two-stage process for visceral adipose tissue (VAT) Treg cells: priming in the spleen, followed by diversification in VAT. This supports the lymphoid-organ and multistep elements, but the paper establishes the model for VAT Tregs, not tissue Tregs generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTCR signaling is thought to contribute to Treg cell accumulation in the brain and VAT.
“As TCR signaling is thought to contribute to Treg cell accumulation in the brain and VAT 27,35”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [35]
The Discussion section, “The TCR, Foxp3 and IL-33 control VAT-Treg cell accumulation” (page unavailable), says a particular TCR could drive Treg expansion or retention in VAT. The cited paper does not establish the corresponding point for the brain, so it supports only the VAT portion of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVAT Treg cells have a role in protecting from metabolic disease.
“VAT Treg cells were analyzed due to their documented unique transcriptome and T cell receptor (TCR) repertoire, as well as their role in protecting from metabolic disease 22,33-36 .”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [35]
VAT Treg cells have a documented unique transcriptome and T cell receptor (TCR) repertoire.
“VAT Treg cells were analyzed due to their documented unique transcriptome and T cell receptor (TCR) repertoire, as well as their role in protecting from metabolic disease 22,33-36 .”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [35]
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Exploring new perspectives in immunology
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A Unique Population: Adipose-Resident Regulatory T Cells
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Regulation of regulatory T cells in cancer
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Two regulatory T cell populations in the visceral adipose tissue shape systemic metabolism
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Regulatory T cells as a therapeutic approach for inflammatory bowel disease
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The dark side of Tregs during aging
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Treg specialization and functions beyond immune suppression
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Self-citationTissue Tregs and Maintenance of Tissue Homeostasis
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PPARγ marks splenic precursors of multiple nonlymphoid-tissue Treg compartments
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Self-citationImportance of the Microenvironment and Mechanosensing in Adipose Tissue Biology
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Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution
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Self-citationStability and Maintenance of Foxp3+ Treg Cells in Non-lymphoid Microenvironments
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- Authors
- Li, C., DiSpirito, J. R., Zemmour, D., Spallanzani, R. G., Kuswanto, W., Benoist, C., & Mathis, D.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Mathis, Diane
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 174
- Issue
- 2
- Pages
- 285-299.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6046274
- OpenAlex
- W2806425229
- Cited by
- 231
- References
- 33
- Citations by year
- 2026: 8 · 2025: 31 · 2024: 41 · 2023: 20 · 2022: 35 · 2021: 31 · 2020: 28 · 2019: 29 · 2018: 8
- FWCI
- 10.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association (1-16-PDF-028, 1-17-PMF-005)
- National Institutes of Health (2R01 DK092541)
- JPB Foundation
- Boehringer Ingelheim (F30AG046045, T32-GM007753)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- visceral adipose tissue, regulatory T cells, T cell receptor transgenic mice, Foxp3, Treg differentiation, microenvironmental cues
- MeSH terms
- Interleukin-1 Receptor-Like 1 Protein, Animals, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Receptors, Antigen, T-Cell, RNA, Spleen, Receptors, Interleukin, Chromatin Assembly and Disassembly, PPAR gamma, Intra-Abdominal Fat, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Single-Cell Analysis, Transcriptome
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