Skin-resident memory T cells mediate delayed-onset drug hypersensitivity reactions in human and mice

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Delayed-onset drug hypersensitivity reactions (DHRs) are a significant cause of morbidity and mortality as they can manifest as severe cutaneous, blistering disease with potentially internal organ involvement. The most life-threatening presentation is Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN). Though there is ample evidence implicating T cells in disease, pathogenesis is largely unknown. Skin-resident memory T cells (TRM) have recently been identified as the predominant T cell population within skin at steady-state. They have also been found to play a protective role against infection and to be directly involved in immune- mediated skin diseases such as psoriasis and contact dermatitis. We therefore propose the hypothesis that skin TRM are causal in delayed-type DHRs. I will use two independent and novel approaches to directly test this hypothesis. The first utilizes multi-spectral immunofluorescence staining and imaging, gene expression profiling and T cell receptor (TCR) sequencing, to interrogate skin TRM cells in formalin-fixed paraffin-embedded (FFPE) skin samples taken from patients with clinically diagnosed and dermatopathologically confirmed cases of SJS/ TEN and healthy human skin controls. The second capitalizes on a recently generated humanized HLA-B*15:02 positive mouse model of SJS/TEN to study skin TRM and other T cell subpopulations in vivo, allowing for deeper mechanistic studies. The data generated through this research should facilitate a better understanding of disease pathogenesis of SJS/TEN and delayed-onset DHRs in general.