T Cells Induce Prolonged Downregulation of Barrier Molecules in a Mouse Model of Allergic Contact Dermatitis

Background: Dysfunction of the skin barrier is regarded as a key event in the initiation and progression of inflammatory skin diseases. In many cases of allergic contact dermatitis (ACD), epidermal-resident memory CD8⁺ T (T_RM) cells play a central role in the immune response to contact allergens. However, if and how allergen-specific CD8⁺ T_RM cells affect the expression of skin barrier molecules is not known. Methods: The expression level of skin barrier molecules was determined by RT-qPCR and immunofluorescence in a mouse model of ACD. The role of CD8⁺ T cells on the expression of skin barrier molecules was investigated by depletion of CD8⁺ cells. Human primary keratinocytes were used to assess the direct effect of IFN-γ and contact allergen on their expression of skin barrier molecules. Results: Sensitization with the contact allergen 1-fluoro-2,4-dinitrobenzene (DNFB) resulted in epidermal accumulation of CD8⁺ T_RM cells and prolonged upregulation of Ifng and downregulation of keratin 5 (Krt5) and Krt14 even after complete macroscopic remission of the inflammatory response. Challenge with DNFB lead to an additionally rapid downregulation of Krt5 and Krt14 and the downregulation of several other skin barrier molecules. Depletion of CD8⁺ cells abolished both the prolonged and rapid downregulation of skin barrier molecules. In keratinocytes, IFN-γ and contact allergen synergistically down-regulated the expression of KRT5 and KRT14. Conclusion: CD8⁺ T_RM cells contribute to a prolonged reduction in the expression of skin barrier molecules, which might exacerbate allergen permeation and the inflammatory response during succeeding exposures of the skin to allergens and antigens.