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Journal article
Glycolysis: An early marker for vancomycin‐specific T‐cell activation
Clinical and experimental allergy, Vol.54(1), pp.21-33
2024
PMID: 38177093
Abstract
Background
Vancomycin, a glycopeptide antibiotic used for Gram-positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA-A*32:01-expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug-reactive T-cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug-specific T-cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug-reactive T-cell clones (TCCs) generated from healthy donors and vancomycin-hypersensitive patients.
Methods
CD4+ and CD8+ vancomycin-responsive TCCs were generated by serial dilution. The Seahorse XFe96 Analyzer was used to measure the extracellular acidification rate (ECAR) as an indicator of glycolytic function. Additionally, T-cell proliferation and cytokine release (IFN-γ) assay were utilised to correlate the bioenergetic characteristics of T-cell activation with in vitro assays.
Results
Model T-cell stimulants induced non-specific T-cell activation, characterised by immediate augmentation of ECAR and rate of ATP production (JATPglyc). There was a dose-dependent and drug-specific glycolytic shift when vancomycin-reactive TCCs were exposed to the drug. Vancomycin-reactive TCCs did not exhibit T-cell cross-reactivity with structurally similar compounds within proliferative and cytokine readouts. However, cross-reactivity was observed when analysing energetic responses; TCCs with prior specificity for vancomycin were also found to exhibit glycolytic switching after exposure to teicoplanin. Glycolytic activation of TCC was HLA restricted, as exposure to HLA blockade attenuated the glycolytic induction.
Conclusion
These studies describe the glycolytic shift of CD4+ and CD8+ T cells following vancomycin exposure. Since similar glycolytic switching is observed with teicoplanin, which did not activate T cells, it is possible the master switch for T-cell activation is located upstream of metabolic signalling.
Details
- Title
- Glycolysis: An early marker for vancomycin‐specific T‐cell activation
- Authors/Creators
- Joshua Gardner - University of LiverpoolSean Hammond - ApconiX Alderley Edge UKRebecca Jensen - University of LiverpoolAndrew Gibson - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsMatthew S. Krantz - Vanderbilt UniversityMichael Ardern-Jones - University of SouthamptonElizabeth J. Phillips - Vanderbilt UniversityMunir Pirmohamed - University of LiverpoolAmy E. Chadwick - University of LiverpoolCatherine Betts - AstraZenecaDean J. Naisbitt - University of Liverpool
- Publication Details
- Clinical and experimental allergy, Vol.54(1), pp.21-33
- Publisher
- John Wiley & Sons Ltd.
- Identifiers
- 991005628869007891
- Copyright
- © 2024 The Authors.
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- Citation topics
- 1 Clinical & Life Sciences
- 1.265 Dermatology - Skin Allergies
- 1.265.1140 Drug Hypersensitivity
- Web Of Science research areas
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- Immunology
- ESI research areas
- Immunology