Metabolic reprogramming of human CD8(+) memory T cells through loss of SIRT1

The expansion of CD8(+)CD28(–) T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8(+)CD28(–) T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8(+)CD28(–) T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD(+)-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8(+)CD28(–) T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8(+)CD28(–) T cells, and inhibiting its activity in resting CD8(+)CD28(+) T cells enhanced glycolytic capacity and granzyme B production as in CD8(+)CD28(–) T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8(+) memory T cell metabolism and activity in humans.