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Whether similar immunopathogenic mechanisms are involved in the responses to clinically relevant contact allergens is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The immune response to cinnamal, \u03c1\u2010phenylenediamine (PPD) and methylisothiazolinone (MI) was studied in a well\u2010established mouse model for allergic contact dermatitis that includes formation of T<jats:sub>RM<\/jats:sub> cells by ELISA, flow cytometry, fluorescence microscopy analyses and cell depletion protocols.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that the formation of CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> epidermal T<jats:sub>RM<\/jats:sub> cells and the inflammatory response are highly allergen\u2010dependent. However, the magnitude of the flare\u2010up responses correlated with the number of epidermal CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells, CXCL1\/CXCL2 release and recruitment of neutrophils to the epidermis. Finally, depletion of CD4<jats:sup>+<\/jats:sup> T cells strongly enhanced the number of epidermal CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells, the flare\u2010up response and the epidermal infiltration of neutrophils for all allergens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>As the first, this study demonstrates that clinically relevant contact allergens have the ability to generate pathogenic, epidermal CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells that recruit neutrophils following re\u2010exposure to the allergen, but that this normally is counteracted by the simultaneous induction of anti\u2010inflammatory CD4<jats:sup>+<\/jats:sup> T 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