Dataset Information

Carbon source availability drives nutrient utilization in CD8⁺ T cells.

ABSTRACT: How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8⁺ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8⁺ T cells, with lactate directly fueling the TCA cycle. In fact, CD8⁺ T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8⁺ T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8⁺ effector T cells.

SUBMITTER: Kaymak I

PROVIDER: S-EPMC10068808 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Carbon source availability drives nutrient utilization in CD8+ T cells.

Kaymak Irem I Luda Katarzyna M KM Duimstra Lauren R LR Ma Eric H EH Longo Joseph J Dahabieh Michael S MS Faubert Brandon B Oswald Brandon M BM Watson McLane J MJ Kitchen-Goosen Susan M SM DeCamp Lisa M LM Compton Shelby E SE Fu Zhen Z DeBerardinis Ralph J RJ Williams Kelsey S KS Sheldon Ryan D RD Jones Russell G RG

Cell metabolism 20220817 9

How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8+ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ T cells, with lactate directly fueling the TCA cycl ...[more]

PMID: 35981545

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Project description:Cells must sense and respond to available nutrients to utilize available resources and establish fungal colonies. Saprophytic microbes harvest carbon from plant biomass, which contain insoluble, complex carbohydrates that must be degraded extracellularly prior to import into the cell. Filamentous fungi can degrade these complex carbohydrates. However, while many single cellular microbes can utilize the building blocks of these insoluble polysaccharides, they frequently are unable to degrade insoluble carbohydrates. Cellobiose is a disaccharide breakdown product of cellulose, the most abundant component of plant biomass. We investigated the genetic regulation of cellobiose utilization in the oleaginous, basidiomycete yeast Rhodotorula (Rhodosporidium) toruloides using a combination of phylogenetic, genetic, and genomic approaches. We tested the closest R. toruloides homolog of the cellulose degradation regulator CLR-2/ClrB for a role in cellobiose utilization. Deletion of this transcription factor, which we named Cbr1, eliminated the ability of cells to grow on media containing cellobiose as the sole carbon source. Although, the role of CLR-2/ClrB is limited to regulating the expression of genes involved in the utilization of cellulose and hemicellulose, Cbr1 plays a role not only in cellobiose utilization, but also utilization of tricarboxylic acid (TCA) cycle intermediates. Transcriptional profiling revealed that the genes activated by Cbr1 included genes encoding beta-glucosidases and transporters. These beta-glucosidases are secreted and are necessary and sufficient for cellobiose utilization, while one of the transporters is required for utilization of the TCA cycle intermediate, citrate. Additionally, Cbr1 inhibits carbon catabolite repression, specifically during utilization of disaccharides, which may have evolved to limit the repression of genes encoding secreted proteins that cleave disaccharides into glucose extracellularly. The co-regulation of cellobiose and TCA cycle utilization with carbon catabolite repression may shed light on alternative methods of the regulation of carbon catabolite repression in fungi.

Dataset Information

Carbon source availability drives nutrient utilization in CD8⁺ T cells.

Publications

Carbon source availability drives nutrient utilization in CD8<sup>+</sup> T cells.

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