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

迟发性药物超敏反应(DHR)是导致发病率和死亡率的重要原因，因为它们可以表现为严重的皮肤起泡疾病，并可能累及内脏。最危及生命的表现是史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症(SJS/TEN)。尽管有充分的证据表明T细胞与疾病有关，但其发病机制很大程度上尚不清楚。皮肤驻留记忆T细胞(TRM)最近被确定为稳定状态下皮肤内的主要T细胞群。它们还被发现对感染起到保护作用，并直接参与免疫介导的皮肤病，如牛皮癣和接触性皮炎。因此，我们提出皮肤TRM是延迟型DHR的因果关系的假设。我将使用两种独立而新颖的方法来直接检验这一假设。第一种利用多光谱免疫荧光染色和成像、基因表达谱和T细胞受体(TCR)测序，询问来自临床诊断和皮肤病理学确诊的SJS/TEN患者和健康皮肤对照的福尔马林固定石蜡包埋(FFPE)皮肤样本中的皮肤TRM细胞。第二个利用最近产生的人源化HLAB*15：02阳性小鼠模型SJS/TEN来研究体内皮肤TRM和其他T细胞亚群，从而进行更深层次的机制研究。通过这项研究产生的数据应该有助于更好地了解SJS/TEN和一般延迟起病的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.