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 (TRM ) 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 TRM cells by ELISA, flow cytometry, fluorescence microscopy analyses and cell depletion protocols. RESULTS: We show that the formation of CD4+ and CD8+ epidermal TRM cells and the inflammatory response are highly allergen-dependent. However, the magnitude of the flare-up responses correlated with the number of epidermal CD8+ TRM cells, CXCL1/CXCL2 release and recruitment of neutrophils to the epidermis. Finally, depletion of CD4+ T cells strongly enhanced the number of epidermal CD8+ TRM 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+ TRM 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.

Epidermal T cell subsets-Effect of age and antigen exposure in humans and mice.

BACKGROUND: Epidermal T cells play a central role in immune surveillance and in inflammatory skin diseases. Major differences in the epidermal T cell composition are found between adult humans and antigen-inexperienced laboratory mice. Whether this is due to inborn species differences, to different environmental exposures, or a combination of the two is a matter of debate. OBJECTIVES: To investigate the role of age and exposure to antigens on epidermal T cell subsets in human and mouse skin. METHODS: We isolated T cells from the epidermis from 19 infants and 26 adults, and determined the frequency of CD4+ and CD8+ αß T cells and γδ T cells by flow cytometry. In addition, we determined the epidermal T cell composition in antigen-inexperienced and antigen-experienced mice. RESULTS: We found that humans are born with very few epidermal T cells. The number increases and the composition changes with age. In antigen-inexperienced mice, the epidermal T cell composition is unaffected by age, but it is dramatically affected by antigen exposure. CONCLUSION: Taken together, we show that antigen exposure, as opposed to age, is the major factor determining the composition of epidermal T cells, suggesting that the skin of antigen-experienced mice better reflects the immunological conditions in human skin.

γδ T cells and inflammatory skin diseases.

Approximately 25% of the population suffers from skin diseases. The most common forms of skin diseases are the inflammatory skin diseases such as allergic contact dermatitis, psoriasis, and atopic dermatitis. These diseases are described as T cell-mediated diseases induced by either allergens or autoantigens. Classically, the focus has been on the role of αß T cells, but it is becoming increasingly clear that γδ T cells play a central role in inflammatory skin diseases. In particular, an important role of IL-17A-producing γδ T cells in these inflammatory skin diseases has been shown in various disease models in mice. Interestingly, various epidermal proteins, which appear to be linked to inflammatory conditions in the skin by yet undescribed mechanisms, are expressed by specific subsets of thymic epithelial cells and mutations in these proteins seem to affect γδ T cell development. The focus of this review is how mutations in epidermal proteins affect γδ T cell development and how γδ T cells, and in particular of IL-17A-producing γδ T cells, contribute to inflammatory skin diseases such as allergic contact dermatitis, psoriasis, and atopic dermatitis.

Increased Production of IL-17A-Producing γδ T Cells in the Thymus of Filaggrin-Deficient Mice.

Mutations in the filaggrin gene (Flg) are associated with increased systemic levels of Th17 cells and increased IL-17A production following antigen exposure in both humans and mice. In addition to Th17 cells, γδ T cells can produce IL-17A. The differentiation of γδ T cells to either IFNγ or IL-17A-producing (γδT17) cells is mainly determined in the thymus. Interestingly, it has been reported that filaggrin is expressed in the Hassall bodies in the human thymic medulla. However, whether filaggrin affects γδ T cell development is not known. Here, we show that filaggrin-deficient flaky tail (ft/ft) mice have an increased number of γδT17 cells in the spleen, epidermis, and thymus compared to wild-type (WT) mice. We demonstrate that filaggrin is expressed in the mouse thymic medulla and that blocking the egress of cells from the thymus results in accumulation of Vγ2+ γδT17 cells in the thymus of adult ft/ft mice. Finally, we find increased T cell receptor expression levels on γδ T cells and increased levels of IL-6 and IL-23 in the thymus of ft/ft mice. These findings demonstrate that filaggrin is expressed in the mouse thymic medulla and that production of Vγ2+ γδT17 cells is dysregulated in filaggrin-deficient ft/ft mice.