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An Optimized Protocol to Analyze Glycolysis and Mitochondrial Respiration in Lymphocytes
Published on: November 21, 2016
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Glycolysis: An early marker for vancomycin-specific T-cell activation
Joshua Gardner1, Sean Hammond2, Rebecca Jensen1
1Department of Pharmacology and Therapeutics, Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.
Summary
Vancomycin-reactive T cells show a specific glycolytic shift upon drug exposure, indicating a metabolic pathway crucial for drug hypersensitivity. This metabolic response, not general T-cell activation, is key to understanding DRESS syndrome.
Area of Science:
- Immunology
- Cellular Metabolism
- Pharmacogenomics
Background:
- Vancomycin, an antibiotic for Gram-positive infections, is linked to DRESS in HLA-A*32:01 individuals.
- T-cell activation in DRESS involves glycolysis, but underlying metabolic processes are unclear.
- Understanding these pathways may reveal mechanisms of drug hypersensitivity versus tolerance.
Purpose of the Study:
- To characterize immunological and metabolic pathways in vancomycin-specific T-cell activation.
- To investigate the role of T-cell metabolism in DRESS pathogenesis using vancomycin.
- To compare drug-reactive T-cell clones from healthy donors and hypersensitive patients.
Main Methods:
- Generated CD4+ and CD8+ vancomycin-responsive T-cell clones (TCCs).
- Measured glycolytic function via extracellular acidification rate (ECAR) using Seahorse XFe96 Analyzer.
- Correlated bioenergetics with T-cell proliferation and IFN-γ cytokine release.
Main Results:
- Non-specific T-cell stimulants caused immediate ECAR and ATP production increases.
- Vancomycin-reactive TCCs exhibited a dose-dependent, drug-specific glycolytic shift.
- Cross-reactivity was observed in energetic responses (glycolytic switching) with teicoplanin, but not in proliferation or cytokine release.
- Glycolytic activation was HLA-restricted, attenuated by HLA blockade.
Conclusions:
- Vancomycin exposure induces a glycolytic shift in CD4+ and CD8+ T cells.
- Similar glycolytic switching with teicoplanin suggests the master T-cell activation switch is upstream of metabolic signaling.
