| Title: |
Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets |
| Authors: |
Shah, Pranali N; Romar, George A; Manukyan, Artür; Ko, Wei-Che; Hsieh, Pei-Chen; Velasquez, Gustavo A; Schunkert, Elisa M; Fu, Xiaopeng; Guleria, Indira; Bronson, Roderick T; Wei, Kevin; Waldman, Abigail H; Vleugels, Frank R; Liang, Marilyn G; Giobbie-Hurder, Anita; Mostaghimi, Arash; Schmidt, Birgitta Ar; Barrera, Victor; Foreman, Ruth K; Garber, Manuel; Divito, Sherrie J |
| Contributors: |
Dermatology; Genomics and Computational Biology; Garber Lab |
| Source: |
The Journal of clinical investigation ; United States |
| Publication Year: |
2024 |
| Collection: |
University of Massachusetts, Medical School: eScholarship@UMMS |
| Subject Terms: |
Allergy; Dermatology; Immunology; Skin; T cells |
| Description: |
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 requires investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRM) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, SJS/TEN and DRESS, and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling and scRNAseq + CITEseq + TCRseq supported in SJS/TEN clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin, along with expanded and non-expanded cytotoxic CD8+ skin TRM. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRM 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 TRM were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced regulatory T cell (Treg) signature compared to MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin like SJS/TEN, yet a pro-Treg signature like MDE. These findings have important implications for fundamental skin immunology and clinical care. |
| Document Type: |
text |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Journal of Clinical Investigation; https://doi.org/10.1172/jci178253; http://hdl.handle.net/20.500.14038/53742; The Journal of clinical investigation |
| DOI: |
10.1172/JCI178253 |
| Availability: |
https://doi.org/10.1172/JCI178253; https://hdl.handle.net/20.500.14038/53742 |
| Rights: |
Copyright © 2024, Shah et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.C3BD544C |
| Database: |
BASE |