Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Australia.
Department of Medicine, Vanderbilt University Medical Centre, Nashville, USA.
Nat Commun. 2024 Oct 8;15(1):8722. doi: 10.1038/s41467-024-52990-3.
Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening cutaneous drug reaction mediated by human leukocyte antigen (HLA) class I-restricted CD8 T cells. For unbiased assessment of cellular immunopathogenesis, here we perform single-cell (sc) transcriptome, surface proteome, and T cell receptor (TCR) sequencing on unaffected skin, affected skin, and blister fluid from 15 SJS/TEN patients. From 109,888 cells, we identify 15 scRNA-defined subsets. Keratinocytes express markers indicating HLA class I-restricted antigen presentation and appear to trigger the proliferation of and killing by cytotoxic CD8 tissue-resident T cells that express granulysin, granzyme B, perforin, LAG3, CD27, and LINC01871, and signal through the PKM, MIF, TGFβ, and JAK-STAT pathways. In affected tissue, cytotoxic CD8 T cells express private expanded and unexpanded TCRαβ that are absent or unexpanded in unaffected skin, and mixed populations of macrophages and fibroblasts express pro-inflammatory markers or those favoring repair. This data identifies putative cytotoxic TCRs and therapeutic targets.
史蒂文斯-约翰逊综合征和中毒性表皮坏死松解症（SJS/TEN）是一种罕见但危及生命的皮肤药物反应，由人类白细胞抗原（HLA）I 类限制性 CD8 T 细胞介导。为了对细胞免疫发病机制进行无偏评估，我们在这里对 15 名 SJS/TEN 患者的未受影响皮肤、受影响皮肤和疱液进行了单细胞(sc)转录组、表面蛋白质组和 T 细胞受体 (TCR)测序。从 109888 个细胞中，我们鉴定出 15 个 scRNA 定义的亚群。角质形成细胞表达表明 HLA I 类限制性抗原呈递的标志物，似乎触发表达颗粒酶 B、穿孔素、LAG3、CD27 和 LINC01871 的细胞毒性 CD8 组织驻留 T 细胞的增殖和杀伤，并且通过 PKM、MIF、TGFβ 和 JAK-STAT 途径发出信号。在受影响的组织中，细胞毒性 CD8 T 细胞表达私人扩增和未扩增的 TCRαβ，这些在未受影响的皮肤中不存在或未扩增，而混杂的巨噬细胞和成纤维细胞群体表达促炎标志物或有利于修复的标志物。该数据确定了潜在的细胞毒性 TCR 和治疗靶标。
