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  3. 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

  • Signal Transduct Target Ther. 2025 Jun 21;10(1):196. doi: 10.1038/s41392-025-02300-0.
Lele Sun 1 2,  Pengcheng Huai 1 2,  Zhenzhen Wang 1 2,  Qing Zhao 1 2,  Yingjie Lin 1 2,  Tingting Liu 1 2,  Xiaotong Xue 1 2,  Suiting Ao 1 2,  Jiabao You 1 2,  Yonghu Sun 1 2,  Zihao Mi 1 2,  Joshua Gardner 3,  Paul J Thomson 3,  Dean J Naisbitt 3,  Xiaoli Meng 3,  Jianjun Liu 4,  Hong Liu 5 6 7 8,  Furen Zhang 9 10 11 12
Affiliations

Affiliations

  • 1 Dermatology Hospital of Shandong First Medical University, Jinan, Shandong, China.
  • 2 Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 3 MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
  • 4 Laboratory of Human Genomics, Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
  • 5 Dermatology Hospital of Shandong First Medical University, Jinan, Shandong, China. [email protected].
  • 6 Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China. [email protected].
  • 7 School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. [email protected].
  • 8 Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. [email protected].
  • 9 Dermatology Hospital of Shandong First Medical University, Jinan, Shandong, China. [email protected].
  • 10 Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China. [email protected].
  • 11 School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. [email protected].
  • 12 Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China. [email protected].
PMID: 40544157 DOI: 10.1038/s41392-025-02300-0
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 CD56low XCL1/2low NK cell subset and an expansion of CD56high XCL1/2high 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.

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