Mia Hamilton Jee

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.

Background: Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal-resident memory CD8(+) T (T-RM) cells play a key role. The mechanisms involved in the activation of CD8(+) T-RM cells during allergic flare-up responses are not understood. Methods: The expression of CD100 and its ligand Plexin B2 on CD8(+) T-RM cells and keratinocytes before and after allergen exposure was determined by flow cytometry and RT-qPCR. The role of CD100 in the inflammatory response during the challenge phase of ACD was determined in a model of ACD in CD100 knockout and wild-type mice. Results: We show that CD8(+) TRM cells express CD100 during homeostatic conditions and up-regulate it following re-exposure of allergen-experienced skin to the experimental contact allergen 1-fluoro-2,4-dinitrobenzene (DNFB). Furthermore, Plexin B2 is up-regulated on keratinocytes following exposure to some contact allergens. We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFN gamma, IL-17A, CXCL1, CXCL2, CXCL5, and IL-1 ss and decreased recruitment of neutrophils to the epidermis. Conclusion: Our study demonstrates that CD100 is expressed on CD8(+) TRM cells and is required for full activation of CD8(+) TRM cells and the flare-up response of ACD.

Background: The junctional adhesion molecule‐like protein (JAML) plays important roles in wound healing and activation of epidermal γδ T cells in mice. Whether JAML plays a role in contact hypersensitivity (CHS), the animal model of allergic contact dermatitis (ACD), is not known.Methods: To examine the role of JAML in CHS, we used various mouse models of CHS in JAML knockout (KO) and wild‐type (WT) mice. Furthermore, the expression of the JAML ligand coxsackievirus and adenovirus receptor (CXADR) on keratinocytes was accessed in vitro and in vivo.Results: JAML KO mice had a diminished inflammatory response during both the sensitization and elicitation phase of CHS and had reduced numbers of CD8⁺ and CD4⁺ T cells in the epidermis. Furthermore, interferon γ (IFNγ), interleukin 1β (IL‐1β) and CXCL10 production were significantly reduced in JAML KO mice during the elicitation phase. We found that CD8⁺ T cells express JAML and that JAML is essential for rapid flare‐up responses to contact allergens. Finally, we show that keratinocytes up‐regulate the JAML ligand CXADR following exposure to contact allergens.Conclusion: Our study is the first to show a central role of JAML in CHS and reveals a potential new target for the treatment of ACD in humans.

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 αβ 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.