Chronic stimulation of CD8 T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells. +This work was funded by National Institutes of Health Grant
U19-AI100627, the Swiss National Science Foundation and the Novartis Foundation for
Medical-Biological Research (S.S.G.), the Australian Cancer Research Foundation (for
the Peter Mac Flow Cytometry and Molecular Genomics facilities) and by the National
Health and Medical Research Council (NHMRC) through Program Grants 1016953 &
1113904, Ideas Grant APP2001719, Australia Fellowship 585490 (C.C.G.), Senior Principal Research Fellowships (1081858, C.C.G., 1139607, A.K.), and CJ Martin Early Career
Fellowship 585518 (I.A.P.)
