Sustained AhR activity programs memory fate of early effector CD8⁺ T cells.

Abstract

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.