Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets
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
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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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 5

Human skin TRM may be sufficient to mediate MDE.

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Human skin TRM may be sufficient to mediate MDE. (A) Number of lymphocyt...
(A) Number of lymphocytes in peripheral blood of MDE patients with or without lymphopenia. Lower limit of healthy depicted as dotted line. (B) Representative H&E images from a lymphopenic MDE patient and healthy control demonstrating similar mononuclear infiltrate in skin. (C) CD3+, CD4+, and CD8+ T cell count per high-powered field (HPF) by immunohistochemistry in lymphopenic MDE patient versus healthy skin. (D) Representative immunohistochemistry images of CD3+, CD4+, and CD8+ T cells from lymphopenic MDE patient and healthy skin. (E) Representative immunofluorescence staining in skin of lymphopenic MDE patient for CD3 (magenta), CD45RO (green), and CD45RA (orange) (left image) and CD3 (magenta), CLA (orange), and CD8 (green) (right image), with DAPI nuclear stain (blue). (F) Percentage of CD45RO+CD3+ T cells and CLA+CD3+ T cells per HPF of lymphopenic MDE patient compared with healthy skin. Scale bars: 100 μm (B, D, and E). (A, C, and F) Lines show median. Significance defined as P < 0.05, 2-tailed Mann-Whitney U test. Only P < 0.05 shown.