biostudies-literatureZhang HCAMS | Chinese Academy of Medical Sciences Initiative for Innovative Medicine ()CAMS | Chinese Academy of Medical Sciences Initiative for Innovative MedicineMOST | National Natural Science Foundation of China (NSFC)Haihe Laboratory of Cell Ecosystem Innovation FundMOST | National Natural Science Foundation of Chinae2317658121https://www.ebi.ac.uk/biostudies/studies/S-EPMC10945852biostudies-literatureUnknown121(11)Identification of mechanisms that program early effector T cells to either terminal effector T (T_eff) or memory T (T_m) cells has important implications for protective immunity against infections and cancers. Here, we show that the cytosolic transcription factor aryl hydrocarbon receptor (AhR) is used by early T_eff cells to program memory fate. Upon antigen engagement, AhR is rapidly up-regulated via reactive oxygen species signaling in early CD8⁺ T_eff cells, which does not affect the effector response, but is required for memory formation. Mechanistically, activated CD8⁺ T cells up-regulate HIF-1α to compete with AhR for HIF-1β, leading to the loss of AhR activity in HIF-1α^high short-lived effector cells, but sustained in HIF-1α^low memory precursor effector cells (MPECs) with the help of autocrine IL-2. AhR then licenses CD8⁺ MPECs in a quiescent state for memory formation. These findings partially resolve the long-standing issue of how T_eff cells are regulated to differentiate into memory cells.Proceedings of the National Academy of Sciences of the United States of AmericaSustained AhR activity programs memory fate of early effector CD8⁺ T cells.PMC10945852822717598238820122HHXBSS000092021-I2M-1-02132322030Liu JZhou NChen JZhang HZhou YZhang QLv JTang KYang ZLi YMa JLuo XYuan WHuang BfalseSustained AhR activity programs memory fate of early effector CD8⁺ T cells.Identification of mechanisms that program early effector T cells to either terminal effector T (T_eff) or memory T (T_m) cells has important implications for protective immunity against infections and cancers. Here, we show that the cytosolic transcription factor aryl hydrocarbon receptor (AhR) is used by early T_eff cells to program memory fate. Upon antigen engagement, AhR is rapidly up-regulated via reactive oxygen species signaling in early CD8⁺ T_eff cells, which does not affect the effector response, but is required for memory formation. Mechanistically, activated CD8⁺ T cells up-regulate HIF-1α to compete with AhR for HIF-1β, leading to the loss of AhR activity in HIF-1α^high short-lived effector cells, but sustained in HIF-1α^low memory precursor effector cells (MPECs) with the help of autocrine IL-2. AhR then licenses CD8⁺ MPECs in a quiescent state for memory formation. These findings partially resolve the long-standing issue of how T_eff cells are regulated to differentiate into memory cells.2024-01-01T00:00:00Z2024 Mar2025-04-20T02:51:18.759Z2025-02-19T03:10:04.45ZS-EPMC109458523843753710.1073/pnas.2317658121