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Nat Commun. 2018 Jan 16;9(1):249. doi: 10.1038/s41467-017-02689-5.

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

Author information

1
Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, St Louis, MO, 63104, USA.
2
Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, St Louis, MO, 63110, USA.
3
Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, St Louis, MO, 63104, USA. guangyong.peng@health.slu.edu.

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.

PMID:
29339767
PMCID:
PMC5770447
DOI:
10.1038/s41467-017-02689-5
[Indexed for MEDLINE]
Free PMC Article

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