1. Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets.
- Author
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Shah, Pranali N., Romar, George A., Manukyan, Artür, Wei-Che Ko, Pei-Chen Hsieh, Velasquez, Gustavo A., Schunkert, Elisa M., Xiaopeng Fu, Guleria, Indira, Bronson, Roderick T., Wei, Kevin, Waldman, Abigail H., Vleugels, Frank R., Liang, Marilyn G., Giobbie-Hurder, Anita, Mostaghimi, Arash, Schmidt, Birgitta A. R., Barrera, Victor, Foreman, Ruth K., and Garber, Manuel
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DRUG allergy , *T cells , *CYTOTOXIC T cells , *T cell receptors , *DRUG eruptions , *SEVERE combined immunodeficiency - Abstract
Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype, and function of pathogenic T cells across the spectrum of severity require investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRMs) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling, and single-cell RNA-sequencing (scRNA-Seq) plus cellular indexing of transcriptomes and epitopes by sequencing (CITESeq) plus T cell receptor sequencing (TCR-Seq) supported clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin along with expanded and nonexpanded cytotoxic CD8+ skin TRM in SJS/TEN. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRMs as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRMs were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced Treg signature compared with MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin as in SJS/TEN, yet a pro-Treg signature as in MDE. These findings have important implications for fundamental skin immunology and clinical care. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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