Cited by 224T-cell and B-cell ImmunologyTelomeres, Telomerase, and SenescenceCancer Immunotherapy and Biomarkers

Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition

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Liu, Xia, Mo, Wei, Ye, Jian, Li, Lingyun, Zhang, Yanping, Hsueh, Eddy C., Hoft, Daniel F., Peng, Guangyong·2018·Nature Communications

Abstract

Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. The molecular processes that occur in responder T cells that are suppressed by Treg cells are unclear. Here we show that human Treg cells initiate DNA damage in effector T cells caused by metabolic competition during cross-talk, resulting in senescence and functional changes that are molecularly distinct from anergy and exhaustion. ERK1/2 and p38 signaling cooperate with STAT1 and STAT3 to control Treg-induced effector T-cell senescence. Human Treg-induced T-cell senescence can be prevented via inhibition of the DNA damage response and/or STAT signaling in T-cell adoptive transfer mouse models. These studies identify molecular mechanisms of human Treg cell suppression and indicate that targeting Treg-induced T-cell senescence is a checkpoint for immunotherapy against cancer and other diseases associated with Treg cells.

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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 [53]

  • 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 [53]

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Authors
Liu, X., Mo, W., Ye, J., Li, L., Zhang, Y., Hsueh, E. C., Hoft, D. F., & Peng, G.
Affiliations
Saint Louis University (US)
Corresponding author
Peng, Guangyong
Venue
Nature Communications
Published
2018-01-16
Volume
9
Issue
1
Pages
249-249
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2782893319
Cited by
224
References
64
Citations by year
2026: 17 · 2025: 40 · 2024: 39 · 2023: 16 · 2022: 30 · 2021: 32 · 2020: 28 · 2019: 13 · 2018: 9
FWCI
8.81
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Cancer Society (RSG‐10‐160‐01‐LIB)
  • Melanoma Research Alliance
  • Washington University in St. Louis
  • National Institutes of Health (AI097852)
  • National Cancer Institute (R01CA184379)
  • National Institute of Allergy and Infectious Diseases (R21AI094478, R21AI097852)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
regulatory T cells, effector T cells, metabolic competition, DNA damage, ERK signaling, p38 MAPK signaling, STAT1, STAT3, DNA damage response, T cell exhaustion, anergy, adoptive T cell therapy, cancer immunotherapy, chronic infection
MeSH terms
DNA Damage, Glucose, Humans, Immunotherapy, Cellular Senescence, MAP Kinase Signaling System, T-Lymphocytes, Regulatory, STAT1 Transcription Factor, STAT3 Transcription Factor

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