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

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.