CD8+ tissue-resident memory T cells recruit neutrophils that are essential for flare-ups in contact dermatitis.

Abstract

BACKGROUND\nAllergic contact dermatitis (ACD) is classically described as a delayed-type hypersensitivity reaction. However, patients often experience flare-ups characterized by itching erythema, edema, and often vesicles occurring within hours after re-exposure of previously sensitized skin to the specific contact allergen. Recent studies have indicated that skin-resident memory T (TRM ) cells play a central role in ACD. However, the pathogenic role of TRM cells in allergen-induced flare-ups is not known.\n\n\nMETHODS\nBy the use of various mouse models and cell depletion protocols, we investigated the role of epidermal TRM cells in flare-up reactions to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene (DNFB). The inflammatory response was measured by changes in ear-thickness and the cellular composition in epidermis was determined by flow cytometry and confocal microscopy. Finally, adaptive transfer and inhibitors were used to determine the role of TRM cells, neutrophils and CXCL1/CXCL2 in the response.\n\n\nRESULTS\nWe show that CD8+ TRM cells initiate massive infiltration of neutrophils in the epidermis within 12 hours after re-exposure to the contact allergen. Depletion of neutrophils before re-exposure to the allergen abrogated the flare-up reactions. Furthermore, we demonstrate that CD8+ TRM cells mediate neutrophil recruitment by inducing CXCL1 and CXCL2 production in the skin, and that blockage of the C-X-C chemokine receptor type 1 and 2 inhibits flare-up reactions and neutrophil infiltration.\n\n\nCONCLUSION\nAs the first, we show that epidermal CD8+ TRM cells cause ACD flare-ups by rapid recruitment of neutrophils to the epidermis.