Ketolysis drives CD8+ T cell effector function through effects on histone acetylation

Luda, Katarzyna M.; Longo, Joseph; Kitchen-Goosen, Susan M.; Duimstra, Lauren R.; Ma, Eric H.; Watson, McLane J.; Oswald, Brandon M.; Fu, Zhen; Madaj, Zachary; Kupai, Ariana; Dickson, Bradley M.; DeCamp, Lisa M.; Dahabieh, Michael S.; Compton, Shelby E.; Teis, Robert; Kaymak, Irem; Lau, Kin H.; Kelly, Daniel P.; Puchalska, Patrycja; Williams, Kelsey S.; Krawczyk, Connie M.; Lévesque, Dominique; Boisvert, François-Michel; Sheldon, Ryan D.; Rothbart, Scott B.; Crawford, Peter A.; Jones, Russell G.

doi:10.1016/j.immuni.2023.07.002

Cited by 43 publications

(15 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As previously reported [9, 10, 36, 67], mobile phase A was LC/MS H 2 O (W6-4, Fisher) with 3% LC/MS grade MeOH (A456-4, Fisher), mobile phase B was LC/MS grade methanol (A456-4, Fisher), and both mobile phases contained 10 mM tributylamine (90780-100ML, Sigma), 15 mM acetic acid, and 0.01% medronic acid (v/v, 5191-4506, Agilent). For the re-equilibration gradient, mobile phase A was kept the same, and mobile phase B was 99% LC/MS grade acetonitrile (A955-4, Fisher).…”

Section: Methodssupporting

confidence: 77%

A diverse proteome is present and enzymatically active in metabolite extracts

House,

Soper-Hopper,

Vincent

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Metabolomics, a foundational tool in metabolism research, relies on the accurate transmittal of biochemical profiles underlying biological phenotypes. Over the years, workflows used in metabolomics have been assumed to remove enzymes to preserve metabolite levels during processing. Here, we uncover a diverse landscape of over 1,000 proteins, strongly enriched for metabolic enzymes, within metabolite extracts generated using common extraction workflows. Moreover, by combining in-extract stable isotope additions and enzyme inhibitors, we demonstrate transaminase activity, which is preventable by protein removal by 3 kDa filtration. We extend these findings to untargeted metabolomics, revealing that both post-extraction formation of glutamate dipeptide and depletion of total glutathione can also be prevented by removing proteins. Finally, we present a simple yet novel workflow that integrates passive filtration for protein removal of crude metabolite extracts as a superior method for broad-coverage metabolomics. Our findings have broad-reaching experimental implications across all fields that use metabolomics and molecular metabolism, especially cancer, immunology, and diabetes research.

show abstract

Section: Methodssupporting

confidence: 77%

A diverse proteome is present and enzymatically active in metabolite extracts

House,

Soper-Hopper,

Vincent

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…Macrophages do not oxidize BHB 52 . However, neurons 53,54 , CD4 + T cells 34,35 , CD8 + T cells 34,36 , and microglia 41 do, results in the formation of ATP and intermediate metabolites, such as acetyl-CoA and succinate. Although S-BHB is oxidized much more slowly than R-BHB 2 , both forms of BHB acid reduced inflammation to a similar degree (Figure 3B), suggesting both R-and S-BHB appear to function as signaling molecules rather than energy metabolites for achieving anti-inflammatory effects.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies suggest that KDs and BHB can improve T cell immune functions in both humans and mice [34][35][36] . To examine the impact of a cyclic KD on age-related immunophenotyping systemically, blood samples were collected and analyzed after a one-year KD intervention at 24 months of age (Supplemental Figure 2A).…”

Section: One-year Kd Reduces Hepatic Chronic Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Nomura,

Murad,

Madhavan

et al. 2023

Preprint

View full text Add to dashboard Cite

Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionallyin vitro. Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB’s anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demon-strate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.

show abstract

“…[46] Ketone bodies also enhance the effector response of cytotoxic CD8 + T cells. [47,48] Amino acid metabolism Amino acid metabolism is essential for macromolecular biosynthesis, energy generation, redox homeostasis, and post-transcriptional modi cation in CD8 + T cells, thereby supporting their proliferation, differentiation, and function. [49][50][51] SLC proteins play a pivotal role in transporting amino acids within T cells, serving as critical components for T cell activation and differentiation.…”

Section: Glucose Metabolismmentioning

confidence: 99%

Metabolic plasticity of T cell fate decision

Pan,

Wang,

Zhang

et al. 2024

Chinese Medical Journal

View full text Add to dashboard Cite

The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells. Upon antigen exposure, T cells undergo metabolic reprogramming, leading to the development of functional effectors or memory populations. However, within the tumor microenvironment (TME), metabolic stress impairs CD8+ T cell anti-tumor immunity, resulting in exhausted differentiation. Recent studies suggest that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy. In this review, we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions. Furthermore, we delved into the different metabolic switches that occur during T cell exhaustion, exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion, ultimately leading to a persistently exhausted state. Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.

show abstract

Ketolysis drives CD8+ T cell effector function through effects on histone acetylation

Cited by 43 publications

References 78 publications

A diverse proteome is present and enzymatically active in metabolite extracts

A diverse proteome is present and enzymatically active in metabolite extracts

A ketogenic diet reduces age-induced chronic neuroinflammation in mice

Metabolic plasticity of T cell fate decision

Contact Info

Product

Resources

About