The immune system relies on specialized “effector” T cells to fight off pathogens. However, in chronic infections such as cancer or HIV, the perpetual activation of these cells can turn them into “exhausted” T cells unable to continue fighting. Scientists have long wondered if and how nutrient preference impacts cell identity. Now, scientists at the Salk Institute and collaborators have discovered that a nutritional switch from acetate to citrate plays a key role in determining T cell fates, shifting them from active effector cells to exhausted cells.
The findings are published in Science in an article titled, “Nutrient-driven histone code determines exhausted CD8+ T cell fates,” and may lead to new therapies that target these nutrient-dependent mechanisms to help T cells stay active and energetically optimized against chronic diseases.
The discovery that different nutrients can change a cell’s gene expression, function, and identity significantly advances scientists’ understanding of the relationship between nutrition and cellular health throughout the body.
“You know the saying, ‘You are what you eat?’ Well, we uncovered a way in which this actually operates in cells,” said Susan Kaech, PhD, senior author of the study and holder of the NOMIS Chair at Salk. “This is really exciting on two levels: on a fundamental level, our findings show that a cell’s function can be directly linked to its nutrition; on a more specific level, this sheds new light on how T cells become dysfunctional or exhausted and what we could do to prevent that.”
Metabolism is a central cellular process that processes nutrients into metabolites and energy. 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.
Which genes are expressed in a cell at any given time determines the behavior and identity of the entire cell. The team 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 discovered 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 validate 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. Seeing these differences in expression of ACLY and ACSS2 then led to a line of questioning about whether the downstream acetyl-CoA derived from these proteins may be determining the formation of exhausted T cells.
“We were shocked and thrilled to find the types of nutrients our cells were using changed their genetic expression and identities, meaning we have a whole new nutrient-dependent process to target with therapeutics that better equip us to fight chronic illness,” said Shixin Ma, PhD, first author of the study and postdoctoral researcher in Kaech’s lab.
Exhausted T cells were bailing on ACSS2 and relying heavily on ACLY, forcing themselves to use more citrate and less acetate to create acetyl-CoA, despite equal availability of both nutrients. 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.
The original nutrient was ultimately determining T cell fate—(1) the metabolic enzyme (ACSS2 or ACLY) determined the nutrient used, (2) the metabolic enzyme determined the location of acetyl-CoA, (3) the location of acetyl-CoA determined what gene-modifying histone acetyltransferases were activated, and (4) those histone acetyltransferases either maintained the effector T cell identity or encouraged the shift to exhausted T cell identity.
The 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.
“Truly, this is a radical concept that hasn’t been seen before,” said Kaech. “We are seeing clear consequences in cellular identity and function based on nutrient preferences by cells. The impact of these findings won’t just be within immunotherapy and immunology—every cell type in the body uses these metabolic processes, so plenty of other discoveries and therapeutic innovations can come out of what we’ve found.”
