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Human regulatory T cells induce T-lymphocyte senescence
Open accessAbstract
Regulatory T (Treg) cells have broad suppressive activity on host immunity, but the fate and function of suppressed responder T cells remains largely unknown. In the present study, we report that human Treg cells can induce senescence in responder naive and effector T cells in vitro and in vivo. Senescent responder T cells induced by human Treg cells changed their phenotypes and cytokine profiles and had potent suppressive function. Furthermore, Treg-mediated molecular control of senescence in responder T cells was associated with selective modulation of p38 and ERK1/2 signaling and cell-cycle–regulatory molecules p16, p21, and p53. We further revealed that human Treg-induced senescence and suppressor function could be blocked by TLR8 signaling and/or by specific ERK1/2 and p38 inhibition in vitro and in vivo in animal models. The results of the present study identify a novel mechanism of human Treg cell suppression that induces targeted responder T-cell senescence and provide new insights relevant for the development of strategies capable of preventing and/or reversing Treg-induced immune suppression.
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Many factors in the tumor microenvironment, including cAMP, glucose competition, and oncogenic stress, can induce senescence of T cells, macrophages, natural killer cells, and dendritic cells.
“The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells.”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [51]
Tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells.
“In addition, tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells [51, 53, 58–63].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [51]
An immune system disorder in the elderly may promote tumor growth and induce T cell senescence, such as an increase in the proportion of tumor-associated macrophages and regulatory T cells.
“Multiple studies have shown that an immune system disorder in the elderly may promote tumor growth and induce T cell senescence, such as an increase in the proportion of tumor-associated macrophages and regulatory T cells (Tregs) [51–55].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [51]
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Metadata
- Authors
- Ye, J., Huang, X., Hsueh, E. C., Zhang, Q., Ma, C., Zhang, Y., Varvares, M. A., Hoft, D. F., & Peng, G.
- Affiliations
- Saint Louis University (US)
- Model Animal Research Center (CN)
- Washington University in St. Louis (US)
- Shandong Medical College (CN)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-09-06
- Volume
- 120
- Issue
- 10
- Pages
- 2021-2031
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3437594
- OpenAlex
- W2149780219
- Cited by
- 198
- References
- 49
- Citations by year
- 2026: 12 · 2025: 32 · 2024: 29 · 2023: 18 · 2022: 11 · 2021: 26 · 2020: 9 · 2019: 11 · 2018: 16 · 2017: 4 · 2016: 9 · 2015: 10 · 2014: 4 · 2013: 4 · 2012: 3
- FWCI
- 2.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society (RSG‐10‐160‐01‐LIB)
- Melanoma Research Alliance
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R21AI097852)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- regulatory T cells, T cell senescence, immunosuppression, p38 MAPK signaling, ERK signaling, p16, p21, p53, naive T cells, effector T cells, cytokine profile
- MeSH terms
- Animals, Cell Communication, Cell Cycle, Humans, Immunity, Innate, Lymphocyte Activation, Neoplasm Proteins, CD4-Positive T-Lymphocytes, Gene Expression, Tumor Suppressor Protein p53, Cytokines, Cellular Senescence, Mice, Knockout, CD8-Positive T-Lymphocytes, Coculture Techniques, Cyclin-Dependent Kinase Inhibitor p16, MAP Kinase Signaling System, T-Lymphocytes, Regulatory, Cyclin-Dependent Kinase Inhibitor p21, Toll-Like Receptor 8, Mice, Primary Cell Culture
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