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Relevance of distinct skin-resident cell populations in human contact allergy

ABSTRACT: Metal allergies are prime examples of delayed hypersensitivity divided in two phases: sensitization and elicitation. Sensitization occurs upon initial contact with the allergen and leads to activation of skin resident cells and formation of metal-reactive T cells. During the elicitation phase, these T cells mount an immune response causing symptoms such as itchy eczema approximately 72 hours after exposure. Research has identified two main mechanisms involved in the initiation of contact hypersensitivity: direct activation of innate immune receptors such as Toll-like receptor 4 by the respective allergen, and conditional innate immune activation via the NLRP3 inflammasome. Elicitation is dominated by the activity of cytotoxic T cells, but it is unclear if only metal-responsive circulating T cells or also tissue-resident T cells contribute. To identify the relevant cell types and signals mediating human nickel hypersensitivity, we used single-cell RNA sequencing of cells from a donor sensitized to nickel (but not chromium) who was epicutaneously exposed to either diluent or both metals for 8 or 72 hours. Our results suggest that nickel exposure specifically activates certain populations of endothelial cells, suprabasal keratinocytes, and CCR7+ dendritic cells within 8 hours, a response not observed with chromium exposure. Skin resident T cells were not involved in the early hypersensitivity response as their gene expression remained unaltered 8 hours after nickel exposure. However, substantial changes in the cutaneous T cell compartments were observed after 72 hours of nickel exposure, including infiltration of SELL+ central memory T cells, effector Tc cells, TH cells, and Treg cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245577 | GEO | 2026/03/16

REPOSITORIES: GEO

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Project description:A convergence of technological breakthroughs in the past decade has facilitated the development of rapid screening tools for biomarkers of toxicant exposure and effect. Platforms using the whole adult organism to evaluate the genome-wide response to toxicants are especially attractive. Recent work demonstrates the feasibility of this approach in vertebrates using the experimentally robust zebrafish model. In the present study, we evaluated gene expression changes in whole adult zebrafish following an acute 24 hour exposure to three metals with known human health risks. Male adult zebrafish were exposed to nickel chloride, cobalt chloride, and sodium dichromate concentrations corresponding to their respective 96 hr LC20, LC40 and LC60. Histopathology was performed on a subset of metal-exposed zebrafish to phenotypically anchor transcriptional changes associated with each metal. Comparative analysis identified subsets of differentially expressed transcripts both overlapping and unique to each metal. Application of gene ontology (GO) and transcription factor enrichment algorithms revealed a number of key biological processes perturbed by metal exposures and the master transcriptional regulators mediating gene expression changes. Metal exposures differentially activated biological processes associated with ribosome biogenesis, proteosomal degradation and p53 signaling cascades, while repressing oxygen-generating pathways associated with amino acid and lipid metabolism. Despite appreciable effects on gene regulation, nickel exposures did not induce any morphological alterations in zebrafish organs and tissues. Histopathological effects of cobalt remained confined to the olfactory system, while chromium targeted the gills, pharynx and intestinal mucosa. A number of enriched transcription factors mediate the observed gene response to metal exposure, including known targets such as p53, HIF1M-oM-^AM-! and the myc oncogene and novel regulatory factors such as XBP1, GATA6 and HNF3M-oM-^AM-". This work uses an experimentally innovative approach to capture global responses to metal exposures and provides mechanistic insights into metal toxicity mechanisms. Metal induced changes in gene expression in zebrafish were measured after 24 h exposures to each of three metals (nickel, chromium or cobalt). A total of 48 arrays were processed - 16 arrays per metal with 4 replicates for each exposure condition (control, low, mid, and high).

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Relevance of distinct skin-resident cell populations in human contact allergy

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