期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 215, 期 1, 页码 51-62出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20161066
关键词
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资金
- Gladstone Institutes
- National Institutes of Health [1DP1DA038043]
- National Science Foundation [1144247]
- Evangelische Studienwerk Villigst, Germany
- University of California, San Francisco-Gladstone Institute of Virology Immunology
- Center for AIDS Research (CFAR), a National Institutes of Health [P30 AI027763]
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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