Memory CD8 + T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function

Abstract

How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8(+) T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8(+) T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8(+) T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8(+) T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8(+) T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness.

De novo acetate production is coupled to central carbon metabolism in mammals

“…The dependence on acetate to supply both nucleocytosolic and mitochondrial acetyl-CoA pools has been identified in multiple cell types, including cancer cells, T cells, and neurons [8][9][10]13,14 . Our study provides evidence for a glucose-derived overflow pathway for acetate metabolism that occurs in mammalian cells.…”

“…Acetate metabolism provides a parallel pathway for acetylcoA production separate from conversion of citrate to acetyl-CoA by ATP citrate lyase (ACLY) and thus acetate allows for protein acetylation and lipogenesis independent of citrate conversation to acetyl-CoA. This pathway is essential in nutrient deprived tumor microenvironments and other diverse contexts but the origin of acetate has been unclear [8][9][10][11][12][13][14] . It has been postulated that acetate may be synthesized de novo in cells [15][16][17][18][19] but the pathways and quantitative reaction mechanisms through which this may occur are unknown.…”

SGLT1 Deficiency Turns Listeria Infection into a Lethal Disease in Mice

“…Lack of SGLT1 may thus compromise glucose uptake, function and survival of granulocytes entering infected tissue with low extracellular glucose concentration. In addition, metabolism can regulate immune functions [37, 38]. Therefore lack of SGLT1 might induce an oxidative metabolism in granulocytes which could limit their function and survival [39].…”

Nutrient sensing, signal transduction and immune responses

“…SCFA signalling through the GPCRs GPR43, GPR41 and GPCR109a ( Figure 3A); GPR41 is expressed primarily on adipocytes, GPR43 is highly expresses on polymorphonuclear leukocytes (PMNs) and lymphocytes, and GPR190a is expressed on various immune cells including neutrophils and macrophages but not lymphocytes [98][99][100][101][102][103]. SCFA can impact upon the differentiation of both CD4 and CD8 T subsets, promoting CD4 regulatory T cell (Treg) formation and optimal CD8 memory T cell responses [104,105]. Tregs are important in maintaining immune homeostasis and Tregs numbers in the colon lamina propria are dependent on the gut microbiome; germ free mice have dramatically reduced Treg numbers in the colon [105,106].…”

“…Acetate is converted to acetyl-CoA, the substrate for acetylation reactions, while butyrate and propionate are inhibitors of histone deacetylases (HDAC) ( Figure 3A). Elevated levels of acetate promotes the acetylation of the glycolytic enzyme GAPDH facilitating elevated glycolytic flux and robust CD8 memory T cell responses [104]. Butyrate and propionate mediated inhibition of HDACs affects histone acetylation in T cells; butyrate/propionate promotes acetylation at the FoxP3 locus in Tregs inducing FoxP3 protein expression [109,110].…”