CD4⁺ T cells inhibit the generation of CD8⁺ epidermal-resident memory T cells directed against clinically relevant contact allergens

Background: CD8⁺ epidermal-resident memory T (T_RM) cells play central roles in local flare-up responses to experimental contact allergens by inducing massive influx of neutrophils to the epidermis upon allergen challenge. Whether similar immunopathogenic mechanisms are involved in the responses to clinically relevant contact allergens is unknown. Methods: The immune response to cinnamal, ρ-phenylenediamine (PPD) and methylisothiazolinone (MI) was studied in a well-established mouse model for allergic contact dermatitis that includes formation of T_RM cells by ELISA, flow cytometry, fluorescence microscopy analyses and cell depletion protocols. Results: We show that the formation of CD4⁺ and CD8⁺ epidermal T_RM cells and the inflammatory response are highly allergen-dependent. However, the magnitude of the flare-up responses correlated with the number of epidermal CD8⁺ T_RM cells, CXCL1/CXCL2 release and recruitment of neutrophils to the epidermis. Finally, depletion of CD4⁺ T cells strongly enhanced the number of epidermal CD8⁺ T_RM cells, the flare-up response and the epidermal infiltration of neutrophils for all allergens. Conclusion: As the first, this study demonstrates that clinically relevant contact allergens have the ability to generate pathogenic, epidermal CD8⁺ T_RM cells that recruit neutrophils following re-exposure to the allergen, but that this normally is counteracted by the simultaneous induction of anti-inflammatory CD4⁺ T cells.