Author:
Gibson Andrew,Ram Ramesh,Gangula Rama,Li Yueran,Mukherjee Eric,Palubinsky Amy M,Campbell Chelsea N,Thorne Michael,Konvinse Katherine C,Choshi Phuti,Deshpande Pooja,Pedretti Sarah,O’Neil Richard T,Wanjalla Celestine N,Kalams Spyros A,Gaudieri Silvana,Lehloenya Rannakoe J,Bailin Samuel S,Chopra Abha,Trubiano Jason A,Peter Jonny G,Mallal Simon A,Phillips Elizabeth J
Abstract
AbstractStevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but lifethreatening cutaneous drug reaction mediated by human leukocyte antigen (HLA) class I-restricted CD8+ T-cells. To obtain an unbiased assessment of SJS/TEN cellular immunopathogenesis, we performed single-cell (sc) transcriptome, surface proteome, and TCR sequencing on unaffected skin, affected skin, and blister fluid from 17 SJS/TEN patients. From 119,784 total cells, we identified 16 scRNA-defined subsets, confirmed by subsetdefining surface protein expression. Keratinocytes upregulated HLA and IFN-response genes in the affected skin. Cytotoxic CD8+ T-cell subpopulations of expanded and unexpanded TCRαβ clonotypes were shared in affected skin and blister fluid but absent or unexpanded in SJS/TEN unaffected skin. SJS/TEN blister fluid is a rich reservoir of oligoclonal CD8+ T-cells with an effector phenotype driving SJS/TEN pathogenesis. This multiomic database will act as the basis to define antigen-reactivity, HLA restriction, and signatures of drug-antigen-reactive T-cell clonotypes at a tissue level.
Publisher
Cold Spring Harbor Laboratory