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Modified Vaccinia Ankara (MVA) was recently approved as a smallpox vaccine. Variola is transmitted by respiratory droplets and MVA immunization by skin scarification (s.s.) protected mice far more effectively against lethal respiratory challenge with vaccinia virus (VACV) than any other route of delivery, and at lower doses. Comparisons of s.s. with intradermal, subcutaneous, or intramuscular routes showed that MVA OVA s.s.-generated T cells were both more abundant and transcriptionally unique. MVA OVA s.s. produced greater numbers of lung Ova-specific CD8 + T RM and was superior in protecting mice against lethal VACV OVA respiratory challenge. Nearly as many lung T RM were generated with MVA OVA s.s. immunization compared to intra-tracheal immunization with MVA OVA and both routes vaccination protected mice against lethal pulmonary challenge with VACV OVA . Strikingly, MVA OVA s.s.-generated effector T cells exhibited overlapping gene transcriptional profiles to those generated via intra-tracheal immunization. Overall, our data suggest that heterologous MVA vectors immunized via s.s. are uniquely well-suited as vaccine vectors for respiratory pathogens, which may be relevant to COVID-19. In addition, MVA delivered via s.s. could represent a more effective dose-sparing smallpox vaccine.

Although memory T cells within barrier tissues can persist as permanent residents, at least some exchange with blood. The extent to which this occurs is unclear. Here we show that memory CD4 + T cells in mouse skin are in equilibrium with the circulation at steady state. These cells are dispersed throughout the inter-follicular regions of the dermis and form clusters with antigen presenting cells around hair follicles. After infection or administration of a contact sensitizing agent, there is a sustained increase in skin CD4 + T-cell content, which is confined to the clusters, with a concomitant CCL5-dependent increase in CD4 + T-cell recruitment. Skin CCL5 is derived from CD11b + cells and CD8 + T cells, with the elimination of the latter decreasing CD4 + T-cell numbers. These results reveal a complex pattern of tissue-retention and equilibration for CD4 + memory T cells in skin, which is altered by infection and inflammation history. Memory T cells are vital responders to skin inflammation, but cell localization and dynamics of exchange with the bloodstream are not clear. Here the authors use parabiosis and intravital microscopy to show that CD4 + memory T cells equilibrate with the circulation and cluster around hair follicles in response to CCL5-dependent responses to viral infection or contact sensitization.

Ambient air particulate matter (PM) induces senescence in human skin cells. However, the underlying mechanisms remain largely unknown. We investigated how epigenetic regulatory mechanisms participate in cellular senescence induced by PM with a diameter <2.5 (PM 2.5 ) in human keratinocytes and mouse skin tissues. PM 2.5 -treated cells exhibited characteristics of cellular senescence. PM 2.5 induced a decrease in DNA methyltransferase (DNMT) expression and an increase in DNA demethylase (ten–eleven translocation; TET) expression, leading to hypomethylation of the p16 INK4A promoter region. In addition, PM 2.5 led to a decrease in polycomb EZH2 histone methyltransferase expression, whereas the expression of the epigenetic transcriptional activator MLL1 increased. Furthermore, binding of DNMT1, DNMT3B, and EZH2 to the promoter region of p16 INK4A decreased in PM 2.5 -treated keratinocytes, whereas TET1 and MLL1 binding increased, leading to decreased histone H3 lysine 27 trimethylation (H3K27Me3) and increased H3K4Me3 in the promoter of p16 INK4A . PM 2.5 -induced senescence involved aryl hydrocarbon receptor (AhR)-induced reactive oxygen species (ROS) production. ROS scavenging dampened PM 2.5 -induced cellular senescence through regulation of DNA and histone methylation. Altogether, our work shows that skin senescence induced by environmental PM 2.5 occurs through ROS-dependent the epigenetic modification of senescence-associated gene expression. Our findings provide information for the design of preventive and therapeutic strategies against skin senescence, particularly in light of the increasing problem of PM 2.5 exposure due to air pollution. Skin damage: counteracting the effects of air pollution Fine particulate matter in polluted air damages skin cells by increasing oxidative stress and the expression of a protein that stops cell division. Jin Won Hyun and colleagues at Jeju National University School of Medicine, South Korea, show that exposure to particulate matter emitted by diesel engines causes skin cell senescence. In previous studies, they reported that particulate matter exposure led to the generation of reactive oxygen species (ROS). This study shows that ROS triggers changes in DNA and histone-modifying enzymes that remove suppressive chemical markers from the gene encoding a protein associated with senescence, p16 INK4 . Interestingly, treatment with the antioxidant N-acetylcysteine reduced both oxidative stress and p16 INK4 expression. These findings could guide the development of new skin-care products that prevent damage due to air pollution.

The role of mouse dermal γδ T cells in inflammatory skin disorders and host defense has been studied extensively. It is known that dendritic epidermal T cells (DETC) have a monomorphic γδ T cell receptor (TCR) and reside in murine epidermis from birth. We asked if dermal γδ cells freely re-circulated out of skin, or behaved more like dermal resident memory T cells (TRM) in mice. We found that, unlike epidermal γδ T cells (DETC), dermal γδ cells are not homogeneous with regard to TCR, express the tissue resident T cell markers CD69 and CD103, bear skin homing receptors, and produce IL-17 and IL-22. We created GFP+: GFP- parabiotic mice and found that dermal γδ T cells re-circulate very slowly-more rapidly than authentic αβ TCR TRM, but more slowly than the recently described dermal αβ TCR T migratory memory cells (TMM). Mice lacking the TCR δ gene (δ-/-) had a significant reduction of 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity (CHS). We created mice deficient in dermal γδ T cells but not DETC, and these mice also showed a markedly reduced CHS response after DNFB challenge. The infiltration of effector T cells during CHS was not reduced in dermal γδ T cell-deficient mice; however, infiltration of Gr-1+CD11b+ neutrophils, as well as ear swelling, was reduced significantly. We next depleted Gr-1+ neutrophils in vivo, and demonstrated that neutrophils are required for ear swelling, the accepted metric for a CHS response. Depletion of IL-17-producing dermal Vγ4+ cells and neutralization of IL-17 in vivo, respectively, also led to a significantly reduced CHS response and diminished neutrophil infiltration. Our findings here suggest that dermal γδ T cells have an intermediate phenotype of T cell residence, and play an important role in primary CHS through producing IL-17 to promote neutrophil infiltration.

Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease, and AD patients are commonly sensitized to house dust mite (HDM). Of the several treatment options available, allergen‐specific immunotherapy (AIT) has been recognized as an effective treatment modality that is directed toward the immunoglobulin E (IgE)‐mediated nature of AD, and subcutaneous administration using HDM is most commonly used for AIT in AD. For patients sensitized to animal (dog or cat) dander, the treatment may not be easy, especially when avoiding the allergen is not possible. Methods This study enrolled patients with AD who were sensitized to cat and/or dog dander and underwent AIT (n = 19). Patients’ medical information was obtained, including past treatment history, treatment duration of AIT, and the progress of treatment. Also, the specific IgE levels and IgG4 levels were measured before and after AIT. Results A total of 19 patients with AD underwent AIT using cat and/or dog dander. The patients consisted of 4 males and 15 females with an average age of 31.74 ± 9.71. Only two patients had AD only, and the other 17 patients had one or more concomitant allergic diseases, such as allergic rhinitis, allergic asthma, or allergic conjunctivitis. Seven patients were not sensitized to HDMs and only sensitized to cat and/or dog dander. The duration of AIT ranged from 2 to 58 months. The symptoms of 17 patients were well‐controlled, requiring only topical treatment and/or oral antihistamines. One patient required systemic cyclosporine, but only of low dose (25 mg/day). The specific IgE levels were decreased (P = .005) and IgG4 levels showed the tendency of increasing after AIT. No adverse events were observed in these patients. Conclusion Although a larger number of patients for a longer follow‐up period are needed to precisely assess the treatment efficacy, AIT using cat and/or dog dander may be an effective treatment option for AD patients, especially for severe AD patients with other respiratory allergic comorbidities who cannot completely avoid the exposure to animal dander. As the sensitization to animal dander, predominantly cat and dog dander, constitutes a significant portion in patients with atopic dermatitis (AD), treatment modalities directed toward the desensitization of these allergens should also be available. While allergen‐specific immunotherapy using cat and/or dog dander is performed in patients with respiratory allergic diseases, there has been no report for AD, and in this study, we found that it was effective in AD as well.

Tissue-resident memory T cells are increasingly being linked to human tissue-specific immune and inflammatory disease. These roles are discussed in this review. Over the past decade, it has become clear that there is an important subset of memory T cells that resides in tissues—tissue-resident memory T (T RM ) cells. There is an emerging understanding that T RM cells have a role in human tissue-specific immune and inflammatory diseases. Furthermore, the nature of the molecular signals that maintain T RM cells in tissues is the subject of much investigation. In addition, whereas it is logical for T RM cells to be located in barrier tissues at interfaces with the environment, these cells have also been found in brain, kidney, joint and other non-barrier tissues in humans and mice. Given the biology and behavior of these cells, it is likely that they have a role in chronic relapsing and remitting diseases of both barrier and non-barrier tissues. In this Review we discuss recent insights into the biology of T RM cells with a particular focus on their roles in disease, both proven and putative.

FABP4 and FABP5 are important for the maintenance, longevity and function of CD8 + tissue-resident memory T cells, which use oxidative metabolism of exogenous free fatty acids to persist in tissues and to mediate protective immunity. Lipid uptake in tissue-resident memory T cells Tissue-resident memory T (T RM ) cells are found in the skin, where they protect the host against pathogens, but it has not been clear how they manage to survive long-term. Thomas Kupper and colleagues now report that these cells are more dependent on exogenous free fatty acid uptake than are central memory and effector memory T cells. They show that T RM cells express high levels of several molecules that mediate the uptake and intracellular transport of lipids, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5), and implicate Fabp4 and Fabp5 as critical mediators of exogenous fatty acid uptake in murine and human T RM cells. Tissue-resident memory T (T RM ) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens 1 , 2 , 3 , 4 . However, the biological pathways that enable the long-term survival of T RM cells are obscure 4 , 5 . Here we show that mouse CD8 + T RM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 ( Fabp4 / Fabp5 ) impairs exogenous free fatty acid (FFA) uptake by CD8 + T RM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (T CM ) cells in lymph nodes. In vitro , CD8 + T RM cells, but not CD8 + T CM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4 / Fabp5 double-knockout CD8 + T RM cells. The persistence of CD8 + T RM cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo . Moreover, skin CD8 + T RM cells that lacked Fabp4 / Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4 / Fabp5 double-knockout CD8 + T RM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8 + T RM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8 + T RM cells, and suggest that CD8 + T RM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.

Head and neck dermatitis (HND) is a form of atopic dermatitis (AD) that affects the seborrheic areas of the body and causes greater quality of life detriments than other types of AD. HND can be challenging to treat since first-line topical therapies may be ineffective or intolerable for long-term use on areas affected by HND while dupilumab may cause dupilumab-associated HND (DAHND). Current evidence implicates fungi, particularly Malassezia spp., in the pathogenesis of HND. Penetration of fungal antigens through the defective AD skin barrier activates the innate and adaptive immune systems to cause cutaneous inflammation via the T helper (Th)17 and/or Th2 axes. Malassezia sensitization may distinguish HND from other forms of AD. Multiple double-blind, placebo-controlled trials have shown antifungals to benefit HND, yet the persistence of symptom relief with sustained use remains unclear. Oral antifungals appear more effective than topical antifungals but may be harmful with long-term use. DAHND may also be fungal-mediated given improvement with antifungals and evidence of an overactive immune response against Malassezia in these patients. Janus kinase inhibitors are effective for HND, including DAHND, but may cause significant side effects when administered systemically. OX40/OX40L inhibitors and tralokinumab may be promising options for HND on the horizon. Demographic and environmental factors influence the host mycobiome and should be considered in future precision-medicine approaches as microbiome composition and diversity are linked to severity of HND.

Background Atopic dermatitis (AD) is a chronic inflammatory skin disease whose pathogenesis, cause, and treatment have been extensively studied. The association of AD with Th2 cytokines is well known; therefore, the analysis of this association is crucial for the diagnosis and treatment of AD. This study aimed to present a new method for measuring protein biomarkers in patients with AD, before and after treatment, using minimally invasive microneedles. Materials and methods First, hyaluronic acid‐loaded microneedle patches (HA‐MNs) for skin sample collection were fabricated. Next, after Institutional Review Board approval, 20 patients with AD were recruited and skin samples were taken before and after treatment using four different sampling techniques: (1) tape stripping, (2) hydrocolloid patches, (3) hollow microneedles, and (4) HA‐MNs. Lastly, proteins were isolated from the collected samples, and AD‐related biomarkers were analyzed by enzyme‐linked immunosorbent assay. Results Proteins were successfully extracted from the skin samples collected by tape stripping, hydrocolloid patches, and HA‐MNs, except hollow microneedles. Interleukin (IL)‐4, IL‐13, and interferon‐γ were detected in the HA‐MNs only. By comparing the biomarker level correlation before and after treatment and the improvement score of the patients, we observed a significant negative correlation between IL‐4 and IL‐13 with an improvement in AD symptoms. Conclusion Overall, our results verified that HA‐MNs can be used to effectively analyze protein levels of biomarkers from skin metabolites of patients with AD and can be applied to monitor the treatment progress of patients with AD in a minimally invasive manner.

Background Classifying diverse skin types is crucial for promoting skin health. However, efficiently identifying and analyzing relevant biomarkers from a vast array of available genetic data is challenging. Therefore, this study aimed to develop a precise and efficient platform for analyzing specific skin biomarkers using quantitative real‐time PCR (qRT‐PCR) with the minimal invasive skin sampling method (MISSM). Materials and methods MISSM was used for RNA extraction from skin samples, followed by qRT‐PCR analysis to quantify the expression of 20 biomarkers associated with skin characteristics (four biomarkers each for five skin characteristics). Noninvasive measurements from 299 Korean participants were utilized to correlate biomarker expression with skin parameters. Statistical analyses were conducted between biomarker expression levels and noninvasive skin measurements to select the relatively best‐performing biomarker for each skin characteristic. Results Collagen type 1 alpha 1 (COL1A1) and moesin (MSN) were identified as skin aging biomarkers. Krüppel‐like factor 4 (KLF4) and serine peptidase inhibitor Kazal type 5 (SPINK5) were identified as skin dryness biomarkers, whereas melan‐A (MLANA) was selected as a biomarker for understanding pigmentation dynamics. Myelin protein zero like 3 (MPZL3) and high mobility group box 2 (HMGB2) were identified as markers of oily skin and skin sensitivity, respectively. Statistically significant correlations were found between the biomarker expression levels and noninvasive skin characteristic measurements. Conclusion This study successfully developed a platform for the precise evaluation of individual skin characteristics using MISSM and qRT‐PCR biomarker analysis. By selecting biomarkers that correlate with noninvasive measurements of skin characteristics, we demonstrated the platform's efficacy in assessing diverse skin conditions.