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

迟发型药物超敏反应（DHR）是发病和死亡的重要原因，因为它们可以表现为严重的皮肤起泡疾病，可能累及内脏器官。最危及生命的表现是Stevens-Johnson综合征/中毒性表皮坏死松解症（SJS/TEN）。虽然有充分的证据表明T细胞参与疾病，但发病机制在很大程度上是未知的。皮肤驻留记忆T细胞（TRM）最近已被确定为稳态下皮肤内的主要T细胞群。还发现它们对感染起保护作用，并直接参与免疫介导的皮肤病，如银屑病和接触性皮炎。因此，我们提出的假设，皮肤TRM是因果关系的延迟型DHR。我将使用两种独立而新颖的方法来直接检验这一假设。第一种方法利用多光谱免疫荧光染色和成像、基因表达谱分析和T细胞受体（TCR）测序，以询问福尔马林固定石蜡包埋（FFPE）皮肤样本中的皮肤TRM细胞，这些皮肤样本取自临床诊断和皮肤病理学确诊的SJS/ TEN病例患者和健康人皮肤对照。第二个利用最近产生的人源化HLA-B*15：02阳性小鼠模型SJS/TEN研究皮肤TRM和其他T细胞亚群在体内，允许更深入的机制研究。通过本研究产生的数据应有助于更好地了解SJS/TEN和一般迟发型DHR的疾病发病机制。

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.