TitleMetabolic reprogramming of human CD8 memory T cells through loss of SIRT1.
Publication TypeJournal Article
Year of Publication2018
AuthorsJeng MY, Hull PA, Fei M, Kwon H-S, Tsou C-L, Kasler H, Ng C-P, Gordon DE, Johnson J, Krogan N, Verdin E, Ott M
JournalJ Exp Med
Date Published2018 Jan 02

The expansion of CD8CD28 T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8CD28 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 CD8CD28 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 CD8CD28 T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8CD28 T cells, and inhibiting its activity in resting CD8CD28 T cells enhanced glycolytic capacity and granzyme B production as in CD8CD28 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.

Alternate JournalJ. Exp. Med.
PubMed ID29191913
PubMed Central IDPMC5748845
Grant ListDP1 DA038043 / DA / NIDA NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
S10 RR028962 / RR / NCRR NIH HHS / United States
T32 AI007334 / AI / NIAID NIH HHS / United States