Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson syndrome and toxic epidermal necrolysis
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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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.
Authors
- Andrew Gibson (ORCID: https://orcid.org/0000-0001-9653-3298)
- Chelsea N. Campbell (ORCID: https://orcid.org/0000-0003-1630-6656)
- Jonny Peter (ORCID: https://orcid.org/0000-0002-2658-0723)
- Samuel Bailin (ORCID: https://orcid.org/0000-0003-4990-1013)
- Phuti Choshi (ORCID: https://orcid.org/0000-0001-8860-9635)
- Rannakoe Lehloenya (ORCID: https://orcid.org/0000-0002-1281-1789)
- Mark W. Fear (ORCID: https://orcid.org/0000-0003-3163-4666)
- Jason A. Trubiano (ORCID: https://orcid.org/0000-0002-5111-6367)
- Yueran Li
- Eric Mukherjee (ORCID: https://orcid.org/0000-0001-8715-1378)
- Katherine C. Konvinse (ORCID: https://orcid.org/0000-0003-2451-9256)
- Amy M. Palubinsky (ORCID: https://orcid.org/0000-0001-9285-6479)
- Sarah Pedretti (ORCID: https://orcid.org/0000-0003-4005-8453)
- Celestine N. Wanjalla (ORCID: https://orcid.org/0000-0001-9159-5414)
- Abha Chopra (ORCID: https://orcid.org/0000-0001-5008-9080)
- Spyros A. Kalams (ORCID: https://orcid.org/0000-0003-0098-7995)
- Simon Alexander Mallal (ORCID: https://orcid.org/0000-0002-7036-1309)
- Silvana Gaudieri
- Elizabeth Jane Phillips (ORCID: https://orcid.org/0000-0002-7623-3383)
- M. C. Thorne
- Richard T. O’Neil (ORCID: https://orcid.org/0000-0002-9734-2343)
- Rama Gangula
- Ramesh Ram (ORCID: https://orcid.org/0000-0002-4827-4778)
- Pooja Deshpande (ORCID: https://orcid.org/0000-0002-2071-4962)
- Fiona Wood (ORCID: https://orcid.org/0000-0001-5427-6588)
Institutions
- Medical University of South Carolina (US)
- University of Cape Town (ZA)
- The University of Melbourne (AU)
- Murdoch University (AU)
- The University of Western Australia (AU)
- Fiona Stanley Hospital (AU)
- Groote Schuur Hospital (ZA)
- Peter Doherty Institute (AU)
- South African Tuberculosis Vaccine Initiative (ZA)
- Austin Health (AU)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-08
- DOI
- https://doi.org/10.1038/s41467-024-52990-3
- Citations
- 24
- Primary Topic
- Drug-Induced Adverse Reactions
- Type
- article
- Field-Weighted Citation Impact
- 10.75
Funders
- Vanderbilt University
- Vanderbilt University Medical Center
- National Institutes of Health
- National Health and Medical Research Council