Type I and II Interferons Drive Abacavir Hypersensitivity via Treg Suppression and T-Cell Enhancement in...

Abacavir (ABC)-induced hypersensitivity is associated with HLA-B*57:01, with tolerance maintained by regulatory T cells (Treg). This study hypothesized that the balance between Treg and CD8⁺ T-cells is influenced by the level of human leucocyte antigen (HLA) expression to determine hypersensitivity versus tolerance to abacavir.

HLA-B*57:01 transgenic (Tg) mice and Tg mice lacking H2-K^bD^b (Tg/KO) were treated with ABC with or without IFN-α or IFN-γ blockade. Immune cell phenotype and functions were assessed via flow cytometry, and splenic transcriptomic profiles were analyzed to evaluate gene expression changes associated with treatment.

ABC treatment of Tg/KO mice, which only express HLA-B*57:01 as an MHC-I allele, led to the expansion of drug-specific CD8⁺ T-cells, enhanced antigen presenting cell (APC) activity, and reduction in Tregs. These changes were accompanied by increased IFN-α levels and plasmacytoid dendritic cell (pDC) maturation. Depletion of pDCs or blocking of IFN-αR, in contrast to IFN-γ blockade, restored Treg populations and diminished CD8⁺ T-cell responses. These findings demonstrate that IFN-α, primarily produced by pDCs, disrupts Treg expansion, whereas IFN-γ predominantly enhances APC maturation and activation. Transcriptomic analysis revealed key genes regulated exclusively by ABC treatment in the presence of both IFN-α and IFN-γ signaling and demonstrated that IFN-α signaling predominantly modulates innate and adaptive immune genes while supporting the downregulation of Treg-related genes.

In vivo upregulation of HLA expression modulates the balance between drug-specific and regulatory T cells, thereby promoting optimal pDC expansion and enhancing IFN-α production, which counteracts Treg-mediated ABC tolerance. IFN-γ secretion by drug-specific CD8⁺ T-cells promoted APC and effector T-cell function that led to the development of ABC-associated hypersensitivity reactions in immunocompetent HLA Tg mice.