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The development of microarray patches for vaccine application has the potential to revolutionise vaccine delivery. Microarray patches (MAP) reduce risks of needle stick injury, do not require reconstitution and have the potential to enhance immune responses using a fractional vaccine dose. To date, the majority of research has focused on vaccine delivery with little characterisation of local skin response and recovery. Here we study in detail the immediate local skin response and recovery of the skin post high density MAP application in 12 individuals receiving 3 MAPs randomly assigned to the forearm and upper arm. Responses were characterised by clinical scoring, dermatoscopy, evaporimetry and tissue viability imaging (TiVi). MAP application resulted in punctures in the epidermis, a significant transepidermal water loss (TEWL), the peak TEWL being concomitant with peak erythema responses visualised by TiVi. TEWL and TiVi responses reduced over time, with TEWL returning to baseline by 48 h and erythema fading over the course of a 7 day period. As MAPs for vaccination move into larger clinical studies more variation of individual subject phenotypic or disease propensity will be encountered which will require consideration both in regard to reliability of dose delivery and degree of inherent skin response.

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that results in constipation (IBS-C) or diarrhoea with abdominal pain, flatulence, nausea and bloating. Kiwifruit (Actinidia spp.) are nutrient-dense fruit with a number of reported health benefits that include lowering glycaemic response, improving cardiovascular and inflammatory biomarkers, and enhancing gut comfort and laxation. This study investigated the effect of consuming three whole Zespri® SunGold kiwifruit (Actinidia chinensis var. chinensis ‘Zesy002’) with or without skin on cytokine production and immune and gut health in healthy people and those with IBS-C symptoms. This study enrolled thirty-eight participants in a 16 week randomized cross-over study (19 healthy and 19 participants with IBS-C). Participants were randomized to consume either three kiwifruit without eating the skin or three kiwifruit including the skin for 4 weeks each, with a 4 week washout in between each intervention. There was a significant decrease in the pro-inflammatory cytokine, TNF-α, for both the healthy and the IBS-C participants when they consumed whole kiwifruit and skin, and also for the healthy participants when they ate whole kiwifruit without the skin (p < 0.001). The kiwifruit interventions increased bowel frequency and significantly reduced the gastrointestinal symptom rating scale constipation and Birmingham IBS pain scores for both participant groups. We have demonstrated that consuming the skin of SunGold kiwifruit might have beneficial effects on gastrointestinal health that are not produced by consuming the flesh alone.

Skin homeostasis is critical to preserve animal integrity. Although the skin of most vertebrates is known to contain a skin-associated lymphoid tissue (SALT), very little is known about skin B-cell responses as well as their evolutionary origins. Teleost fish represent the most ancient bony vertebrates containing a SALT. Due to its lack of keratinization, teleost skin possesses living epithelial cells in direct contact with the water medium. Interestingly, teleost SALT structurally resembles that of the gut-associated lymphoid tissue, and it possesses a diverse microbiota. Thus, we hypothesized that, because teleost SALT and gut-associated lymphoid tissue have probably been subjected to similar evolutionary selective forces, their B-cell responses would be analogous. Confirming this hypothesis, we show that IgT, a teleost immunoglobulin specialized in gut immunity, plays the prevailing role in skin mucosal immunity. We found that IgT ⁺ B cells represent the major B-cell subset in the skin epidermis and that IgT is mainly present in polymeric form in the skin mucus. Critically, we found that the majority of the skin microbiota are coated with IgT. Moreover, IgT responses against a skin parasite were mainly limited to the skin whereas IgM responses were almost exclusively detected in the serum. Strikingly, we found that the teleost skin mucosa showed key features of mammalian mucosal surfaces exhibiting a mucosa-associated lymphoid tissue. Thus, from an evolutionary viewpoint, our findings suggest that, regardless of their phylogenetic origin and tissue localization, the chief immunoglobulins of all mucosa-associated lymphoid tissue operate under the guidance of primordially conserved principles.

Lambrecht and Hammad discuss how microbial diversity or dysbiosis influences epithelial barrier tissues and the impact of such interactions on the development of allergic disease. The immunology of the hygiene hypothesis of allergy is complex and involves the loss of cellular and humoral immunoregulatory pathways as a result of the adoption of a Western lifestyle and the disappearance of chronic infectious diseases. The influence of diet and reduced microbiome diversity now forms the foundation of scientific thinking on how the allergy epidemic occurred, although clear mechanistic insights into the process in humans are still lacking. Here we propose that barrier epithelial cells are heavily influenced by environmental factors and by microbiome-derived danger signals and metabolites, and thus act as important rheostats for immunoregulation, particularly during early postnatal development. Preventive strategies based on this new knowledge could exploit the diversity of the microbial world and the way humans react to it, and possibly restore old symbiotic relationships that have been lost in recent times, without causing disease or requiring a return to an unhygienic life style.

Allergic diseases have in common a dysfunctional epithelial barrier, which allows the penetration of allergens and microbes, leading to the release of type 2 cytokines that drive allergic inflammation. The accessibility of skin, compared with lung or gastrointestinal tissue, has facilitated detailed investigations into mechanisms underlying epithelial barrier dysfunction in atopic dermatitis (AD). This Review describes the formation of the skin barrier and analyzes the link between altered skin barrier formation and the pathogenesis of AD. The keratinocyte differentiation process is under tight regulation. During epidermal differentiation, keratinocytes sequentially switch gene expression programs, resulting in terminal differentiation and the formation of a mature stratum corneum, which is essential for the skin to prevent allergen or microbial invasion. Abnormalities in keratinocyte differentiation in AD skin result in hyperproliferation of the basal layer of epidermis, inhibition of markers of terminal differentiation, and barrier lipid abnormalities, compromising skin barrier and antimicrobial function. There is also compelling evidence for epithelial dysregulation in asthma, food allergy, eosinophilic esophagitis, and allergic rhinosinusitis. This Review examines current epithelial barrier repair strategies as an approach for allergy prevention or intervention.

Atopic dermatitis (AD) is a chronic inflammatory skin disease in which the skin barrier function is disrupted. In this inflammatory AD environment, cytokines are upregulated, but the cytokine effect on the AD skin barrier is not fully understood. We aimed to investigate the influence of Th2 (IL-4, IL-13, IL-31) and pro-inflammatory (tumor necrosis factor alpha (TNF-α)) cytokines on epidermal morphogenesis, proliferation, differentiation, and stratum corneum lipid properties. For this purpose, we used the Leiden epidermal model (LEM) in which the medium was supplemented with these cytokines. Our results show that IL-4, IL-13, IL-31, and TNF-α induce spongiosis, augment TSLP secretion by keratinocytes, and alter early and terminal differentiation-protein expression in LEMs. TNF-α alone or in combination with Th2 cytokines decreases the level of long chain free fatty acids (FFAs) and ester linked ω-hydroxy (EO) ceramides, consequently affecting the lipid organization. IL-31 increases long chain FFAs in LEMs but decreases relative abundance of EO ceramides. These findings clearly show that supplementation with TNF-α and Th2 cytokines influence epidermal morphogenesis and barrier function. As a result, these LEMs show similar characteristics as found in AD skin and can be used as an excellent tool for screening formulations and drugs for the treatment of AD.

The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication 1 . Clinical and experimental data suggest that the latter mode of control—termed cancer–immune equilibrium 1 —can be maintained for prolonged periods of time, possibly up to several decades 2 – 4 . Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer–immune equilibrium in these tissue compartments remain unclear. Here, using a mouse model of transplantable cutaneous melanoma 5 , we show that tissue-resident memory CD8 + T cells (T RM cells) promote a durable melanoma–immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (~40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69 + CD103 + T RM cells correlated with this spontaneous disease control. By contrast, mice deficient in T RM formation were more susceptible to tumour development. Despite being tumour - free at the macroscopic level, mice frequently harboured melanoma cells in the epidermal layer of the skin long after inoculation, and intravital imaging revealed that these cells were dynamically surveyed by T RM cells. Consistent with their role in melanoma surveillance, tumour-specific T RM cells that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of T RM cells triggered tumour outgrowth in a proportion (~20%) of mice with occult melanomas, demonstrating that T RM cells can actively suppress cancer progression. Our results show that T RM cells have a fundamental role in the surveillance of subclinical melanomas in the skin by maintaining cancer–immune equilibrium. As such, they provide strong impetus for exploring these cells as targets of future anticancer immunotherapies. A transplantable mouse model of persistent cutaneous melanoma shows that immune-mediated tumour suppression can result in a state of melanoma–immune equilibrium, and that tissue-resident memory T cells are essential drivers of this equilibrium state.

Hair follicle–derived cytokines control the tropism and retention of memory T cells in the skin and promote lymphoma. The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis through chemokine production. We demonstrate that CD4 + and CD8 + skin-resident memory T cells (T RM cells), which are responsible for long-term skin immunity, reside predominantly within the hair follicle epithelium of the unperturbed epidermis. T RM cell tropism for the epidermis and follicles is herein termed epidermotropism. Hair follicle expression of IL-15 was required for CD8 + T RM cells, and IL-7 for CD8 + and CD4 + T RM cells , to exert epidermotropism. A lack of either cytokine in the skin led to impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4 + T RM lymphoma cell localization depended on the presence of hair follicle–derived IL-7. These findings implicate hair follicle–derived cytokines as regulators of malignant and non-malignant T RM cell tissue residence, and they suggest that the cytokines may be targeted therapeutically in inflammatory skin diseases and lymphoma.

In naive individuals, sensory neurons directly detect and respond to allergens, leading to both the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response 1 , 2 . In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch 3 – 7 . Although these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naive state is unknown. Here we describe a γδ T cell–IL-3 signalling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal γδ T cell subset 8 , termed GD3 cells, that produces its hallmark cytokine IL-3 to promote allergic itch and the initiation of the allergic immune response. Mechanistically, IL-3 acts on Il3ra -expressing sensory neurons in a JAK2-dependent manner to lower their threshold for allergen activation without independently eliciting itch. This γδ T cell–IL-3 signalling axis further acts by means of STAT5 to promote neuropeptide production and the initiation of allergic immunity. These results reveal an endogenous immune rheostat that sits upstream of and governs sensory neuronal responses to allergens on first exposure. This pathway may explain individual differences in allergic susceptibility and opens new therapeutic avenues for treating allergic diseases. A γδ T cell–IL-3 signalling axis is defined that controls the allergen responsiveness of cutaneous sensory neurons, leading to evidence for an immune rheostat that governs sensory neuronal responses to allergens on first exposure.

Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1β were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.