Bruno Lucas: “Type 1 interferon-induced Foxo1 down-regulation is a key contributor to T-cell aging and exhaustion”

Aging is a complex process affecting many aspects of mammalian biology, including the immune system. Indeed, age-related alterations in the immune system make the elderly more susceptible to infectious diseases and tumors, resulting in increased morbidity and mortality. In addition, the recent SARS-coV-2 outbreak has reemphasized that the effectiveness of vaccination is significantly reduced in the elderly population, limiting efficient preventive prophylaxis. It is therefore crucial to understand the impact of the aging process on the immune system. Foxo family transcription factors are critical at the crossroads of various processes, such as metabolism, quiescence, cell survival and cell differentiation.Although in Caenorhabditis elegans, Drosophila melanogaster and Hydra vulgaris, continuous high activity of Foxo family members extends their lifespan, the involvement of Foxo proteins in mammalian aging remains to be determined. We have found that Foxo1 expression is progressively downregulated in mouse T cells with age and that this decrease imprints their transcriptional signature. Comparison of the T-cell compartment of old wild-type (WT) mice (22 months) with that of young adult mice (3 months) deficient or proficient in Foxo1 expression in T cells has allowed us to assess the full consequences of the loss of Foxo1 expression on T-cell aging. Finally, as adoptive transfer of T cells from young to old animals lead to their accelerated aging, we have sought to identify the T-cell extrinsic factors leading to the decrease of Foxo1 expression in T cells and to their subsequent aging.