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

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.