Elucidating CD4+ and CD8+ T-cell involvement in patients with vancomycin-induced DRESS

Gardner, Joshua, Martinez-Rivera, Silvia, Line, James, Thomson, Paul, Clarke, Elsie, Gibson, Andrew, Krantz, Matthew S., Ardern-Jones, Michael, Phillips, Elizabeth J. and Naisbitt, Dean J. (2025) Elucidating CD4+ and CD8+ T-cell involvement in patients with vancomycin-induced DRESS. Toxicological Sciences, 206 (2), 420-432. (doi:10.1093/toxsci/kfaf074).

Abstract

Vancomycin, a glycopeptide antibiotic used to treat severe Gram-positive bacterial infections, is associated with the development of drug reaction with eosinophilia and systemic symptoms (DRESS) in individuals expressing HLA-A∗32:01. Previous studies have identified the potential role of T-cells using HLA-A∗32:01-positive healthy donor models. However, DRESS pathogenesis remains poorly defined, and a deeper mechanistic understanding is required to aid the diagnosis and prediction of vancomycin-induced DRESS. The present study aims to elucidate CD4+ and CD8+ T-cell involvement within the pathogenesis of vancomycin-induced DRESS following the isolation and functional study of cloned T-cells from hypersensitive patients. CD4+ and CD8+ vancomycin-responsive T-cell clones (TCCs) were generated by serial dilution from peripheral blood mononuclear cells collected from suspected vancomycin-DRESS patients. Functionality of drug-responsive TCCs was assessed using T-cell proliferation ([3H]-thymidine). Cytokine analysis was performed using intracellular cytokine staining, enzyme-linked immunospot assay, and LEGENDplex immunoassays. Vancomycin-responsive TCCs expressing CD4+ and CD8+ phenotypes were successfully generated from suspected vancomycin-DRESS patients (n = 3). CD45RO+ memory T-cells were the primary activated population, with both CD4+ and CD8+ T-cells associated with the release of IFN-γ, IL-5, IL-13, granzyme B, and perforin. Vancomycin-responsive CD4+ and CD8+ T-cells are activated by direct, pharmacological interactions, with antigen presentation possible through HLA class I and HLA class II molecules. This study provides in vitro evidence for the dual role of antigen-specific CD4+ and CD8+ T-cells within the pathogenesis of vancomycin-induced DRESS. This has been demonstrated following the generation of cloned T-cells with strong vancomycin specificity from patients presenting with vancomycin-DRESS and positive for expression of HLA-A∗32:01.

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Contributors

Author: Michael Ardern-Jones

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