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Loss of SIRT1 in Memory T Cells During Aging

Melanie Ott

SANTA FE, NM--March 10, 2015--Graduate student Mark Jeng delivers an oral presentation of his project "Loss of SIRT1 promotes metabolic reprogramming in memory T cells during aging and chronic infections" at the annual Keystone Symposium: Biology of Sirtuins. He received a UCSF Graduate Division Travel award to sponsor his attendance at this conference.



The accumulation of CD8+CD28- T cells—a population of terminally differentiated effector T cells—is one of the most consistent and pronounced changes observed in humans as they age or in those with chronic infections. Despite their ubiquitous presence in humans, much of their fate and function remain unclear. Here, we find that human CD8+CD28- T cells post-transcriptionally downregulate the expression of SIRT1, a protein deacetylase known as a central energy sensor and metabolic regulator in muscle and liver cells. Using Seahorse XF technology, we demonstrate that resting human CD8+CD28- T cells possess a greater glycolytic capacity as compared to naïve and CD8+CD28+ memory T cells, thus supporting the concept that these cells are not exhausted, and instead represent a population of highly reactive cytotoxic effector cells with innate-like properties. Loss of SIRT1 is associated with increased protein expression of HIF1α and the increased expression of rate-limiting glycolysis factors such as GLUT1, Phosphofructokinase, and Pyruvate Kinase. Treatment with resveratrol, a SIRT1 activator, reverses the enhanced glycolytic capacity and suppresses the cytotoxic activity of CD8+CD28- T cells, indicating that loss of SIRT1, metabolic reprogramming, and enhanced cytotoxicity in these cells are linked. Collectively, our findings describe SIRT1 as a new factor that is critical for cell fate change in memory T cells during aging and chronic infections.