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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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-06-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02300-0 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Lele Sun |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e5afd5eb1d7b4401a48af3af894805fe |
| institution | OA Journals |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-e5afd5eb1d7b4401a48af3af894805fe2025-08-20T02:10:38ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-06-0110111410.1038/s41392-025-02300-0TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivityLele Sun0Pengcheng Huai1Zhenzhen Wang2Qing Zhao3Yingjie Lin4Tingting Liu5Xiaotong Xue6Suiting Ao7Jiabao You8Yonghu Sun9Zihao Mi10Joshua Gardner11Paul J. Thomson12Dean J. Naisbitt13Xiaoli Meng14Jianjun Liu15Hong Liu16Furen Zhang17Dermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityMRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of LiverpoolMRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of LiverpoolMRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of LiverpoolMRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of LiverpoolLaboratory 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 SingaporeDermatology Hospital of Shandong First Medical UniversityDermatology Hospital of Shandong First Medical UniversityAbstract 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.https://doi.org/10.1038/s41392-025-02300-0 |
| spellingShingle | 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 TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity Signal Transduction and Targeted Therapy |
| title | TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity |
| title_full | TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity |
| title_fullStr | TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity |
| title_full_unstemmed | TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity |
| title_short | TSC22 domain family member 3 links natural killer cells to CD8+ T cell-mediated drug hypersensitivity |
| title_sort | tsc22 domain family member 3 links natural killer cells to cd8 t cell mediated drug hypersensitivity |
| url | https://doi.org/10.1038/s41392-025-02300-0 |
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