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

Xia Liu, Wei Mo, Jian Ye, Lingyun Li, Yanping Zhang, Eddy C. Hsueh, Daniel F. Hoft and Guangyong Peng ()
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Xia Liu: Saint Louis University School of Medicine
Wei Mo: Saint Louis University School of Medicine
Jian Ye: Saint Louis University School of Medicine
Lingyun Li: Saint Louis University School of Medicine
Yanping Zhang: Saint Louis University School of Medicine
Eddy C. Hsueh: Saint Louis University School of Medicine
Daniel F. Hoft: Saint Louis University School of Medicine
Guangyong Peng: Saint Louis University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02689-5

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