Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1.
Mark Y JengPhilip A HullMingjian FeiHye-Sook KwonChia-Lin TsouHerbert G KaslerChe-Ping NgDavid E GordonJeffrey JohnsonNevan KroganEric VerdinMelanie M OttPublished in: The Journal of experimental medicine (2017)
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.
Keyphrases
- transcription factor
- nk cells
- oxidative stress
- signaling pathway
- type diabetes
- ischemia reperfusion injury
- metabolic syndrome
- working memory
- cell proliferation
- blood pressure
- heart rate variability
- pi k akt
- dna methylation
- binding protein
- small molecule
- electronic health record
- data analysis
- amino acid
- genome wide identification
- anti inflammatory