Liu et al. found that Treg cells outcompete responding T cells for glucose, triggering activation of ATM (a key regulator of the DNA damage response) in responding cells and resulting in T cell senescence. Senescence was found to be controlled by MAPK and STAT1/3 signaling and the cell cycle regulators p53 and p16. Senescent T cells are molecularly distinct from exhausted or anergic T cells and exhibit immunosuppressive activity. Inhibition of the ATM or STAT1/3 pathways reduced Treg-mediated T cell senescence in vivo, indicating a possible strategy for immunotherapy.

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.

Author Info: (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 I

Author Info: (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 Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, St Louis, MO, 63104, USA. (3) Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, St Louis, MO, 63104, USA. (4) Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, St Louis, MO, 63104, USA. (5) Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, St Louis, MO, 63110, USA. (6) Department of Surgery, Division of General Surgery, Saint Louis University School of Medicine, St Louis, MO, 63110, USA. (7) Department of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Saint Louis University School of Medicine, St Louis, MO, 63104, USA. (8) 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.