Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets
Pranali N. Shah, … , Manuel Garber, Sherrie J. Divito
Pranali N. Shah, … , Manuel Garber, Sherrie J. Divito
Published July 23, 2024
Citation Information: J Clin Invest. 2024;134(17):e178253. https://doi.org/10.1172/JCI178253.
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Research Article Dermatology Immunology

Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets

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 (CITE-Seq) 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.

Authors

Pranali N. Shah, George A. Romar, Artür Manukyan, Wei-Che Ko, Pei-Chen Hsieh, Gustavo A. Velasquez, Elisa M. Schunkert, Xiaopeng Fu, Indira Guleria, Roderick T. Bronson, Kevin Wei, Abigail H. Waldman, Frank R. Vleugels, Marilyn G. Liang, Anita Giobbie-Hurder, Arash Mostaghimi, Birgitta A.R. Schmidt, Victor Barrera, Ruth K. Foreman, Manuel Garber, Sherrie J. Divito

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Figure 7

Skin TRMs mediate an MDE-like reaction in mice in the absence of circulating T cells.

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Skin TRMs mediate an MDE-like reaction in mice in the absence of circula...
(A) Schematic of drug challenge experiment. Endpoint: 107 days. (B) Ear thickness (mean + SEM shown). (C) Representative histology. Scale bars: 200 μm (gray); 50 μm (black). (D) Total number of CD8+ T cells in ear skin. (E) Number of CD3+ T cells, CD8+ T cells, and effector CD8+ T cells (CD44hiCD62Llo) in blood. (F) Percentage of functional CD8+ T cells in ear skin of mice treated or not with FTY720. (A–F) Each experiment was repeated at least twice. Pooled results from 2 independent experiments shown. (D–F) By flow cytometry. Lines show median. (D and E) Significance defined as P < 0.05, Kruskal-Wallis test followed by Dunn’s multiple-comparisons test. (F) Nonsignificant, P > 0.05; 2-tailed Mann-Whitney U test.