Type I and II Interferons Drive Abacavir Hypersensitivity via Treg Suppression and T‐Cell Enhancement in Immunocompetent HLA ‐Transgenic Mice
Year: 2025
Type: article
Abstract: ABSTRACT Background 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. Methods HLA‐B*57:01 transgenic (Tg) mice and Tg mice lacking H2‐K b D 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. Results 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. Conclusions 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.
Source: Allergy
DOI: 10.1111/all.70189
Authors: SuJin Hwang, Telly Sepahpour, Stephanie Kortchak, Kirthiram Krishnaveni Sivakumar, Spyros Karaiskos, Ngoc Pham, Yura Jang, Montserrat Puig, Michael Norcross
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,300
OpenAlex ID: W4417535282