A Distinct Function of Regulatory T Cells in Tissue Protection
Open accessAbstract
Regulatory T (Treg) cells suppress immune responses to a broad range of non-microbial and microbial antigens and indirectly limit immune inflammation-inflicted tissue damage by employing multiple mechanisms of suppression. Here, we demonstrate that selective Treg cell deficiency in amphiregulin leads to severe acute lung damage and decreased blood oxygen concentration during influenza virus infection without any measureable alterations in Treg cell suppressor function, antiviral immune responses, or viral load. This tissue repair modality is mobilized in Treg cells in response to inflammatory mediator IL-18 or alarmin IL-33, but not by TCR signaling that is required for suppressor function. These results suggest that, during infectious lung injury, Treg cells have a major direct and non-redundant role in tissue repair and maintenance-distinct from their role in suppression of immune responses and inflammation-and that these two essential Treg cell functions are invoked by separable cues.
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The epidermal growth factor receptor ligand amphiregulin is a key factor of tissue Treg cells to maintain homeostasis or induce tissue regeneration in a diverse set of tissues, including lung, muscle, and brain.
“Several publications identified the epidermal growth factor receptor ligand amphiregulin as a key factor of tissue Treg cells to maintain homeostasis or induce tissue regeneration in a diverse set of tissues, including lung, muscle, and brain [447, 448].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [448]
The Results section reports that Treg-cell-derived amphiregulin protects lung tissue after influenza infection, and the Introduction discusses amphiregulin expression in muscle Treg cells and a reported muscle-repair finding. The cited paper does not establish the claimed role in brain tissue, and its direct evidence for tissue protection is limited to the injured lung rather than homeostasis or regeneration across all three tissues. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn acute injury settings, Treg cell-derived Areg is independent of Treg cell-mediated immunosuppression and acts on tissue-resident mesenchymal cells and stem cells, not immune cells.
“In these settings, Treg cell-derived Areg is notably independent of Treg cell-mediated immunosuppression, and acts on tissue-resident mesenchymal cells and stem cells - not immune cells 25,26,28 .”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [25]
The Results section (“Amphiregulin Deficiency Does Not Affect Treg Cell Suppressor Function”; page unavailable) reports that Treg-derived amphiregulin was dispensable for suppressor function. The Introduction proposes a direct tissue-repair role involving parenchymal cells, but our copy does not establish that Areg acts specifically on tissue-resident mesenchymal cells and stem cells, or exclude effects on all immune cells (searched: mesenchymal, stem cells). (LLM, conf=0.87)
Experimental — accuracy not yet measuredAreg Fl/Fl and Areg Fl/Fl Foxp3 YFP-cre mice do not differ in terms of immune infiltration in the setting of tissue damage and Treg cells from these mice exhibit similar functionalities in vitro.
“prior work 25,28 and data in this study find that Areg Fl/Fl and Areg Fl/Fl Foxp3 YFP-cre mice do not differ in terms of immune infiltration in the setting of tissue damage and Treg cells from these mice exhibit similar functionalities in vitro.”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [25]
The Results section, “Amphiregulin Deficiency Does Not Affect Treg Cell Suppressor Function” (page unavailable), reports similar in vitro suppression by amphiregulin-sufficient and -deficient Treg cells. The influenza-infection Results section (page unavailable) reports comparable virus-specific T-cell responses, but does not establish that immune infiltration overall was the same; it also reports increased lymphoid aggregation in mice lacking Treg-derived amphiregulin. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTreg cells support tissue homeostasis and regeneration, ranging from regulating metabolic parameters in adipose tissue to potentiating tissue repair in skeletal muscles, lung tissue, or brain.
“They have been shown to support tissue homeostasis and regeneration, ranging from regulating metabolic parameters in the adipose tissue to potentiating tissue repair [444-446], e.g., in skeletal muscles [447], lung tissue [448], or brain [449].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [448]
Treg cell-derived amphiregulin (Areg) promotes repair after acute tissue injury.
“Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury.”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [25]
Treg cells protect from epithelial cell injury by both interacting with immune cells to suppress inflammation and by producing epithelial growth factors that signal to non-immune cells.
“Together, these studies suggest that Treg cells protect from epithelial cell injury by both interacting with immune cells to suppress inflammation and by producing epithelial growth factors that signal to non-immune cells.”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [25]
Areg production by Treg cells is independent of TCR signaling.
“consistent with prior studies suggesting Areg production by Treg cell is independent of TCR signaling 25 .”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [25]
Early damage-associated inflammatory mediators released upon tissue injury such as IL-18 and IL-33 activate Areg production in Treg cells, whereas TCR signaling is dispensable for Areg production.
“early damageassociated inflammatory mediators released upon tissue injury such as IL-18 and IL-33, activate Areg production in Treg cells, whereas TCR signaling is dispensable for Areg production 25”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [25]
The tissue repair function of Treg cells is distinct from immunosuppressive effects.
“The tissue repair function of Treg cells is distinct from immunosuppressive effects 25”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [25]
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- Authors
- Arpaia, N., Green, J. A., Moltedo, B., Arvey, A., Hemmers, S., Yuan, S., Treuting, P. M., & Rudensky, A. Y.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Washington (US)
- Corresponding author
- Rudensky, Alexander Y.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 162
- Issue
- 5
- Pages
- 1078-1089
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4603556
- OpenAlex
- W1945156854
- Cited by
- 991
- References
- 42
- Citations by year
- 2026: 79 · 2025: 95 · 2024: 99 · 2023: 84 · 2022: 108 · 2021: 103 · 2020: 104 · 2019: 95 · 2018: 86 · 2017: 69 · 2016: 65 · 2015: 4
- FWCI
- 36.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (P30CA008748)
- National Institute of Allergy and Infectious Diseases (R37AI034206, R01AI034206)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- regulatory T cells, tissue repair, amphiregulin, influenza, acute lung injury, IL-18, IL-33, alarmins, oxygen deficiency, lung inflammation
- MeSH terms
- Animals, Disease Models, Animal, Humans, Influenza, Human, Lung, Lymphocyte Activation, Mice, Inbred C57BL, Suppressor Factors, Immunologic, Autoimmunity, T-Lymphocytes, Regulatory, Mice, Amphiregulin
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