Conserved epigenetic hallmarks of T-cell age

Abstract As the immune system ages, the protective capacity from established immunological memory wanes over time and is often referred to as immune senescence. Yet the molecular hallmarks of lymphocyte age and replicative senescence remain largely undefined. Here we report our use of a multi-lifetime murine model of repeat vaccination to define a core epigenetic signature coupled to memory T cells that evade replicative senescence. Through adoptive transfer and boosting over a period of approximately four mouse lifetimes, memory T cells became enriched for repressive DNA methylation programs at cell cycle regulators including the canonical senescence gene P19 Arf(CDKN2A/2B locus – human P14 ARF). The senescence-resistance program was progressively acquired throughout phycological and non-physiological aging of murine T cells, leading to the development of a lymphocyte epigenetic clock that can be used to accurately measure a T cell’s age. Application of this clock in physiologically aged human polyclonal and CMV-specific T cells correlated with age-estimates using established epigenetic chronologic clocks. Moreover, T-cell clock-associated senescence-resistance programs were highly enriched in human malignancies of lymphoid origin, specifically delineating known T-cell acute lymphoblastic leukemia (T-ALL) subtypes and revealing non-physiological aging of HOXA9 and MLL pediatric leukemias (estimated to be ~100 years old). Discovery of the senescence-resistance epigenetic clock provides a novel molecular hallmark for describing physiological and non-physiological lymphocyte age.