TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity

TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity

Abstract Severe cutaneous adverse drug reactions (SCARs) are life-threatening diseases, which are associated with human leukocyte antigen (HLA) risk variants. However, the low positive predictive values of HLA variants suggest additional factors influence disease susceptibility. Using dapsone hypers...

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Main Authors: Lele Sun, Pengcheng Huai, Zhenzhen Wang, Qing Zhao, Yingjie Lin, Tingting Liu, Xiaotong Xue, Suiting Ao, Jiabao You, Yonghu Sun, Zihao Mi, Joshua Gardner, Paul J. Thomson, Dean J. Naisbitt, Xiaoli Meng, Jianjun Liu, Hong Liu, Furen Zhang
Format: Article
Language:English
Published: Nature Publishing Group 2025-06-01
Series:Signal Transduction and Targeted Therapy
Online Access:https://doi.org/10.1038/s41392-025-02300-0
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Summary:Abstract Severe cutaneous adverse drug reactions (SCARs) are life-threatening diseases, which are associated with human leukocyte antigen (HLA) risk variants. However, the low positive predictive values of HLA variants suggest additional factors influence disease susceptibility. Using dapsone hypersensitivity syndrome (DHS) as a paradigm for SCARs, we show that the DHS patients harbor a sex-related global reduction in blood NK cells, contributing to the higher incidence of reactions in females. Single-cell RNA sequencing revealed a decrease in the immunoregulatory CD56 low XCL1/2 low NK cell subset and an expansion of CD56 high XCL1/2 high NK cell subsets with an effector phenotype in DHS patients compared to dapsone-tolerant individuals. Functionally, interleukin-15 superagonist-induced activation of NK cells exacerbated SCARs-like symptoms in a murine model. Mechanistically, TSC22 domain family member 3 (TSC22D3) deficiency enhanced NK cell effector function, shifting the immune response from CD4+ T cell to CD8+ T cell function. These results demonstrate that TSC22D3-regulated NK cells play a critical role in predisposing to drug hypersensitivity reactions, bridging innate and adaptive immune dysregulation in SCARs pathogenesis. Our study highlights the importance of NK cell heterogeneity and TSC22D3 in immune-mediated hypersensitivity disorders, offering potential therapeutic targets for SCARs and related conditions.
ISSN:2059-3635

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