Abstract
Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are often artificially high, representing hyperglycaemic levels rarely present in vivo. We show here that reducing glucose concentration to physiological levels in culture differentially impacted on virus-specific compared to generically activated human CD8 T cell responses. In virus-specific T cells, limiting glucose availability significantly reduced the frequency of effector-cytokine producing T cells, but promoted the upregulation of CD69 and CD103 associated with an increased capacity for tissue retention. In contrast the functionality of generically activated T cells was largely unaffected and these showed reduced differentiation towards a residency phenotype. Furthermore, T cells being cultured at physiological glucose concentrations were more susceptible to viral infection. This setting resulted in significantly improved lentiviral transduction rates of primary cells. Our data suggest that CD8 T cells are exquisitely adapted to their niche and provide a reminder of the need to better mimic physiological conditions to study the complex nature of the human CD8 T cell immune response.
Highlights
Glucose is a key metabolite for rapidly dividing cells
We present data demonstrating that lowering the glucose concentration to a physiological level had a profound effect on virus-specific T cell responses, reducing the number of effector cytokine producing cells and promoting a resident memory phenotype
CD3-activated) or using a selection of immunodominant peptides derived from two common human viral infections; Epstein–Barr Virus (EBV) as an example of a chronic infection and Influenza A virus (Flu) as an example of an acute resolved infection
Summary
Glucose is a key metabolite for rapidly dividing cells. Upon T cell receptor-mediated activation, Tcells undergo metabolic reprogramming, switching from predominantly relying on oxidative phosphorylation (OXPHOS) fuelled by fatty acid oxidation, to significantly upregulating glycolysis to sustain metabolically demanding effector functions and proliferation [1]. Despite the net ATP production from glycolysis being low compared to OXPHOS, glycolysis yields an important carbon source for the generation of nucleic acids, amino acids and phospholipids while leaving biosynthetic building blocks, such as fatty acids and amino acids, intact for being incorporated into cellular components [2]. Glycolysis has a direct impact on the production of the key T cell effector cytokine, interferon gamma (IFN-γ), by promoting expression through epigenetic changes [3]. T cell exhaustion, which is a main driver of failed
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