T cell exhaustion is a poorly defined state in which these immune cells become ineffective, less responsive to antigens. It is seen most evidently in the contexts of persistent viral infection and cancer, but exhausted T cells are also present in older people. A common theme in all of these situations is replication stress, T cells forced into greater replication in response to the circumstances they find themselves in. Replication stress also leads to greater numbers of senescent T cells, another noteworthy problem. In the context of aging replication stress occurs over time because the supply of new T cells is greatly reduced, a consequence of the atrophy of the thymus, while the body still tries to maintain the same overall population size of T cells.
At the end of the day, restoring the hematopoietic system and the thymus in order to produce a youthful supply of new T cells is probably a necessary component of any attempt to fix the issues of the aged immune system. Senescent T cells can be destroyed using senolytic drugs. But can anything be done regarding T cell exhaustion directly? In today's research materials, it is suggested that the exhausted state might be prevented or reversed by altering aspects of nutrient processing in T cells, though the best target mechanism to achieve results analogous to the genetic manipulations that postpone T cell exhaustion shown here remains to be determined.
Your immune cells are what they eat
Nutrients provide the resources for all cellular activities, but they must first be broken down into smaller molecules called metabolites. Metabolites have many uses, including promoting epigenetic regulation, a process that changes the shape of a cell's DNA to alter the accessibility of different genes. Which genes are expressed in a cell at any given time then determines the behavior and identity of the entire cell. Researchers wondered: Could this change in metabolism be responsible for the epigenetic changes that turn effector T cells into exhausted T cells? Is there a link between nutrition and exhausted T cell differentiation? One of the most important and common metabolites is acetyl-CoA, which both effector and exhausted T cells make - but with one interesting difference. Exhausted T cells tend to make their acetyl-CoA using a protein called ACLY that uses citrate, rather than using a protein called ACSS2 that uses acetate.
The preferential activity of citrate-using-ACLY in exhausted T cells and acetate-using-ACSS2 in effector T cells piqued the team's curiosity, leading them to genetically investigate the production of these metabolic proteins in both T cell subtypes. They found that ACSS2 gene expression was most highly expressed in functional T cells, but was drastically reduced in exhausted T cells in both mouse and human tissue samples. In contrast, ACLY genes were expressed similarly in both effector and exhausted T cells - with slightly greater expression in the exhausted cells. This suggested that T cells needed to express ACSS2 to maintain a functional state and that with exhaustion comes a greater reliance on ACLY.
To verify their findings, they went into the T cells and deleted ACLY and ACSS2 genes one at a time - discovering that the loss of ACLY boosted anti-tumor T cell activity, while the loss of ACSS2 did the opposite and reduced T cell efficacy. Upon closer inspection, the researchers noticed that two distinct pools of otherwise identical acetyl-CoA were piling up in different locations in the nucleus - where the cell's DNA is stored - based on whether it was derived from acetate via ACSS2 or from citrate via ACLY. Each nutrient-specific pile was then linked to unique histone acetyltransferases, which are proteins that reshape DNA and influence which genes are expressed to change cellular behavior and identity. This novel link between nutrition and cell identity offers a new explanation for exhausted T cell identity and in turn offers a multitude of new targets for future therapeutics that could keep T cells turned "on" longer.
Nutrient-driven histone code determines exhausted CD8+ T cell fates
Exhausted T cells (TEX) in cancer and chronic viral infections undergo metabolic and epigenetic remodeling, impairing their protective capabilities. However, the impact of nutrient metabolism on epigenetic modifications that control TEX differentiation remains unclear. We showed that TEX cells shifted from acetate to citrate metabolism by downregulating acetyl-CoA synthetase 2 (ACSS2) while maintaining ATP-citrate lyase (ACLY) activity. This metabolic switch increased citrate-dependent histone acetylation, mediated by histone acetyltransferase KAT2A-ACLY interactions, at TEX signature-genes while reducing acetate-dependent histone acetylation, dependent on p300-ACSS2 complexes, at effector and memory T cell genes. Nuclear ACSS2 overexpression or ACLY inhibition prevented TEX differentiation and enhanced tumor-specific T cell responses. These findings unveiled a nutrient-instructed histone code governing CD8+ T cell differentiation, with implications for metabolic- and epigenetic-based T cell therapies.
View the full article at FightAging
