Glycolytic metabolism of CD8⁺ T-cells affects susceptibility to human leukocyte antigen-mediated abacavir-induced hypersensitivity

BACKGROUND AND PURPOSE: Drug hypersensitivity reactions (DHRs) associated with a specific human leukocyte antigen (HLA) allotype do not manifest uniformly in all individuals within an HLA model population. This scenario highlights the complexity of predicting drug hypersensitivity reaction risk without considering additional factors. Furthermore, conducting prospective clinical studies of drug hypersensitivity reactions in humans is unfeasible. Therefore, this study aimed to prospectively evaluate HLA-mediated drug hypersensitivity reactions by using a unique transgenic mouse line harbouring HLA-B*57:01 (B*57:01-Tg) and performing abacavir-induced hypersensitivity reactions. EXPERIMENTAL APPROACH: B*57:01-Tg mice or their littermates were orally administered either an abacavir-containing or a vehicle-only diet. Subsequently, analyses were performed on isolated CD8⁺ T-cells collected from the lymph nodes, ear biopsies, or plasma of these mice. KEY RESULTS: RNA sequencing and proteomic data analyses performed on the isolated CD8⁺ T-cells demonstrated that the expression levels of several glycolytic enzymes, including hexokinase 2, were significantly up-regulated in abacavir-treated B*57:01-Tg mice. Moreover, the glycolytic rate and metabolite production significantly increased in these mice. Although treatment with the pyruvic acid carrier inhibitor UK5099 did not affect CD8⁺ T-cell activation, inhibiting glycolysis using 2-deoxy-D-glucose or diet-based calorie restriction attenuated the increase in IFN-γ-secreting effector memory CD8⁺ T-cells. Consequently, this attenuation prevented CD8⁺ T-cell dermal infiltration in abacavir-treated B*57:01-Tg mice. CONCLUSION AND IMPLICATIONS: Overall, these results suggest the indispensable role of glycolytic CD8⁺ T-cell metabolism in HLA-mediated abacavir-induced hypersensitivity reactions, which may further determine susceptibility to HLA-mediated drug hypersensitivity reactions in humans.