Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson syndrome and toxic epidermal necrolysis

Andrew Gibson, Ramesh Ram, Rama Gangula, Yueran Li, Eric Mukherjee, Amy M. Palubinsky, Chelsea N. Campbell, Michael Thorne, Katherine C. Konvinse, Phuti Choshi, Pooja Deshpande, Sarah Pedretti, Mark W. Fear, Fiona M. Wood, Richard T. O’Neil, Celestine N. Wanjalla, Spyros A. Kalams, Silvana Gaudieri, Rannakoe J. Lehloenya, Samuel S. Bailin, Abha Chopra, Jason A. Trubiano, Jonny G. Peter, Simon A. Mallal and Elizabeth J. Phillips ()
Additional contact information
Andrew Gibson: Murdoch University
Ramesh Ram: Murdoch University
Rama Gangula: Vanderbilt University Medical Centre
Yueran Li: Murdoch University
Eric Mukherjee: Vanderbilt University Medical Centre
Amy M. Palubinsky: Vanderbilt University Medical Centre
Chelsea N. Campbell: Vanderbilt University Medical Centre
Michael Thorne: Murdoch University
Katherine C. Konvinse: Vanderbilt University Medical Centre
Phuti Choshi: Groote Schuur Hospital
Pooja Deshpande: Murdoch University
Sarah Pedretti: University of Cape Town Lung Institute
Mark W. Fear: University of Western Australia
Fiona M. Wood: University of Western Australia
Richard T. O’Neil: Medical University of South Carolina
Celestine N. Wanjalla: Vanderbilt University Medical Centre
Spyros A. Kalams: Vanderbilt University Medical Centre
Silvana Gaudieri: Murdoch University
Rannakoe J. Lehloenya: University of Cape Town
Samuel S. Bailin: Vanderbilt University Medical Centre
Abha Chopra: Murdoch University
Jason A. Trubiano: University of Melbourne
Jonny G. Peter: Groote Schuur Hospital
Simon A. Mallal: Murdoch University
Elizabeth J. Phillips: Murdoch University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52990-3

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