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J Exp Med. 2018 Jan 2;215(1):51-62. doi: 10.1084/jem.20161066. Epub 2017 Nov 30.

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

Jeng MY1,2, Hull PA1,3, Fei M1,2, Kwon HS1,2, Tsou CL1, Kasler H1,4, Ng CP1,4, Gordon DE1,5, Johnson J1,5, Krogan N1,5, Verdin E1,4, Ott M6,2.

Author information

Gladstone Institutes, San Francisco, CA.
Department of Medicine, University of California, San Francisco, San Francisco, CA.
Westfälische Wilhelms-Universität Münster, Münster, Germany.
The Buck Institute for Research on Aging, Novato, CA.
Quantitative Biology Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA.
Gladstone Institutes, San Francisco, CA


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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