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.
Highlights
Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections
We identify that MAPK ERK1/2 and p38 signaling functionally cooperate with transcription factors STAT1/STAT3 to control responder T-cell senescence induced by human Treg cells
We found that co-culture with γδ Treg cells markedly induced activation and phosphorylation of ataxia-telangiectasia mutated protein (ATM) and DNA damage molecules checkpoint kinase 2 (CHK2), H2AX, and 53BP1 in both responder CD4+ and CD8+ T cells (Fig. 1c, d)
Summary
Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. 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. There are other two states of T-cell dysfunction, exhaustion, and anergy, which have been identified in chronic infection, cancer, and autoimmune diseases[19,20] Both exhausted and anergic T cells have defective effector functions, but with distinct regulatory mechanisms. Treg cells initiate the nuclear kinase ataxia-telangiectasia mutated protein (ATM)-
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