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

  • Author(s): Jeng, Mark Y
  • Hull, Philip A
  • Fei, Mingjian
  • Kwon, Hye-Sook
  • Tsou, Chia-Lin
  • Kasler, Herb
  • Ng, Che-Ping
  • Gordon, David E
  • Johnson, Jeffrey
  • Krogan, Nevan
  • Verdin, Eric
  • Ott, Melanie
  • et al.
Abstract

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.

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