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

• Published in: The Journal of clinical investigation 2024-09, Vol.134 (17), p.1-17
• Main 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
• Format: Article
• Language: English
• Subjects: Antigenic determinants; Antigens; CD8 antigen; Complications and side effects; Cytotoxicity; Development and progression; Disease; Drug allergy; Eosinophilia; Epitopes; Gene expression; Genotype & phenotype; Health aspects; Hypersensitivity (delayed); Immune response; Immunological memory; Lymphocytes; Lymphocytes T; Massachusetts; Medical research; Medicine, Experimental; Memory cells; Microscopy; Morbidity; Mortality; Pathogenesis; Phenotypes; Physiological aspects; Skin; Skin diseases; Stevens-Johnson syndrome; T cell receptors; T cells; Toxic epidermal necrolysis; Transcriptomes
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI178253

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.