Skin Dendritic Cells Research Articles

The role of dendritic cells in the instruction of helper T cells in the allergic march.

Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells - type 2 helper T (Th2) cells and follicular helper T (TFH) cells - in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signaling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.

IL-4 acts on skin-derived dendritic cells to promote the TH2 response to cutaneous sensitization and the development of allergic skin inflammation

Atopic dermatitis is characterized by scratching and a TH2-dominated local and systemic response to cutaneously encountered antigens. Dendritic cells (DCs) capture antigens in the skin and rapidly migrate to draining lymph nodes (dLNs) where they drive the differentiation of antigen-specific naive T cells. We sought to determine whether non-T-cell-derived IL-4 acts on skin-derived DCs to promote the TH2 response to cutaneously encountered antigen and allergic skin inflammation. DCs from dLNs of ovalbumin (OVA)-exposed skin were analyzed by flow cytometry and for their ability to polarize OVA-specific naive CD4+ T cells. Skin inflammation following epicutaneous sensitization of tape-stripped skin was assessed by flow cytometry of skin cells and real-time quantitative PCR of cytokines. Cytokine secretion and antibody levels were evaluated by ELISA. Scratching upregulated IL4 expression in human skin. Similarly, tape stripping caused rapid basophil-dependent upregulation of cutaneous Il4 expression in mouse skin. Invitro treatment of DCs from skin dLNs with IL-4 promoted their capacity to drive TH2 differentiation. DCs from dLNs of OVA-sensitized skin of Il4-/- mice and CD11c-CreIl4rflox/- mice, which lack IL-4Rα expression in DCs (DCΔ/Δll4ra mice), were impaired in their capacity to drive TH2 polarization compared with DCs from controls. Importantly, OVA-sensitized DCΔ/Δll4ra mice demonstrated impaired allergic skin inflammation and OVA-specific systemic TH2 response evidenced by reduced TH2 cytokine secretion by OVA-stimulated splenocytes and lower levels of OVA-specific IgE and IgG1 antibodies, compared with controls. Mechanical skin injury causes basophil-dependent upregulation of cutaneous IL-4. IL-4 acts on skin DCs that capture antigen and migrate to dLNs to promote their capacity for TH2 polarization and drive allergic skin inflammation.

Separable nanocomposite hydrogel microneedles for intradermal and sustained delivery of antigens to enhance adaptive immune responses

Vaccines play a critical role in combating infectious diseases and cancers, yet improving their efficacy remains challenging. Here, we introduce a separable nanocomposite hydrogel microneedle (NHMN) patch designed for intradermal and sustained delivery of ovalbumin (OVA), a model antigen, to enhance adaptive immune responses. The NHMN patch consists of an array of OVA-loaded microneedles made from photo-cross-linked methacrylated hyaluronic acid and laponite (LAP), supported by a hyaluronic acid backing. The incorporation of LAP not only enhances the mechanical strength of the pure hydrogel microneedles but also significantly prolongs OVA release. Furthermore, in vitro cell experiments demonstrate that NHMNs effectively activate dendritic cells without compromising cell viability. Upon skin penetration, NHMNs detach from the backing as the hyaluronic acid rapidly dissolves upon contact with the skin interstitial fluid, thereby acting as antigen reservoirs to release antigens to abundant skin dendritic cells. NHMNs containing 0.5% w/v LAP achieved a 15-day OVA release in vivo. Immunization studies demonstrate that the intradermal and sustained release of OVA via NHMNs elicited stronger and longer-lasting adaptive immune responses compared to conventional bolus injection. Given its easy to use, painless and minimally invasive features, the NHMN patch shows promise in improving vaccination accessibility and efficacy against a range of diseases. Statement of significanceThe study introduces a separable nanocomposite hydrogel microneedle (NHMN) patch. This patch consists of an array of ovalbumin (OVA, a model antigen)-loaded microneedles made from photo-cross-linked methacrylated hyaluronic acid and laponite, with a hyaluronic acid backing, designed for intradermal and sustained delivery of antigens. This patch addresses several key challenges in traditional vaccination methods, including poor antigen uptake and presentation, and rapid systematic clearance. The incorporation of laponite enhances mechanical strength of microneedles, promotes dendritic cell activation, and significantly slows down antigen release. NHMN-based vaccination elicits stronger and longer-lasting adaptive immune responses compared to conventional bolus injection. This NHMN patch holds great potential for improving the efficacy, accessibility, and patient comfort of vaccinations against a range of diseases.

Psychodermatology of Chronic Pruritus: An Overview of the Link Between Itch and Distress.

Chronic pruritus (CP) is defined as an unpleasant sensation causing a desire to scratch and lasting > 6 weeks. It has a multifactorial etiology but is more frequently associated with chronic inflammatory dermatoses and systemic disorders. Psychogenic pruritus and neurological disorders are other less common etiologies, while, in some patients, it is idiopathic. CP appears to be processed by non-histaminergic pathway, contributing to its complexity and therapeutic challenge. Moreover, regardless of the etiology, it is multidimensional, including cognitive, motivational and affective components. There is a close link between psychological distress and pruritus, with particular clinical expression in chronic inflammatory dermatoses, involving the activation of the hypothalamic-pituitary-adrenal axis (and its cutaneous equivalent), the sympathetic nervous system, the release of hormones and peptides, the role of immune cells(T and B cells, macrophages) and immune-related cells in the skin (mast cells, dendritic cells and keratinocytes). Moreover, there is strong evidence that psychological factors influence the experience of pruritus. CP can also cause psychiatric disorders, including but not limited to anxiety and depression, and also lead to significant quality of life (QoL) impairment. Thereby, although a psychodermatological assessment should ideally be carried out in the context of a specific psychodermatology consultation, a brief mental health assessment could be part of the general dermatological approach to these patients. Considering that mental health, QoL and pruritus are closely linked, psychotherapeutic interventions and/or psychotropic drugs should thus be considered in some patients as an adjunct to the pharmacological treatment of CP.

Langerhans cells and gamma delta Т-lymphocytes in the pathogenesis of psoriasis

Psoriasis is a frequently occurring inflammatory skin disease. Fundamental research into the pathogenesis of psoriasis has significantly expanded our understanding of skin immunology, which has enabled the introduction of innovative and highly effective therapies. Psoriasis is a largely T-lymphocyte-mediated disease in which activation of innate immune cells and pathogenic T cells leads to inflammation and hyperproliferation of keratinocytes. Langerhans cells like dendritic cells (DCs), which play an important role in the immune system, are mainly distributed in the epidermis. Since human and mouse skin DC subpopulations share common ontogenetic characteristics, we can further investigate the role of DCs in psoriatic inflammation in mice. γδT cells are an unconventional population of T-lymphocytes that play an indispensable role in host defense, immune surveillance, and immune system homeostasis. Although γδT cells constitute only a small fraction of the total T cell pool, emerging evidence suggests that aberrantly activated γδT cells may play a role in the pathogenesis of psoriasis. Dermal γδT cells are the major IL-17-producing cells in the skin that respond to IL-23 stimulation. In addition, γδT cells have characteristics of memory cells that mediate repeated episodes of psoriatic inflammation. This review discusses the mechanisms by which Langerhans cells and γδT cells participate in the pathogenesis of psoriasis.

A CFSE-Based Assay to Monitor Skin Dendritic Cell Migration to Draining Lymph Nodes in Infected Mice

A CFSE-Based Assay to Monitor Skin Dendritic Cell Migration to Draining Lymph Nodes in Infected Mice

A CFSE-Based Assay to Monitor Skin Dendritic Cell Migration to Draining Lymph Nodes in Infected Mice

A CFSE-Based Assay to Monitor Skin Dendritic Cell Migration to Draining Lymph Nodes in Infected Mice

Intradermal Vaccination with Vididencel in MRD+ AML-Patients Leads to Increase in Antigen Presenting Cells and T-Cells to the Injection Site, Visualized Using Imaging Mass Cytometry, Showing Local Immune Cell Interactions Leading to Systemic Immune Responses

Background. Vididencel is an allogeneic leukemia-derived dendritic cell vaccine being developed as maintenance treatment in AML patients. Intradermal vaccination using vididencel is known to induce a local skin reaction, with local antigen processing by skin dendritic cells and direct presentation to T cells as well as dendritic cells, crawling out of the skin and presentation of the antigen in the draining lymph nodes for a full-blown immune response. It was previously shown that vididencel is able to induce an influx of immune cells in the skin using standard immunohistochemistry (van de Loosdrecht, 2018). In a phase 2 study vididencel was investigated as AML maintenance treatment after induction of CR1 with chemotherapy (ADVANCE-II, Clintrials.gov: NCT03697707). Using imaging mass cytometry up to 43 markers can be assessed in the same tissue section, to allow in depth analysis of the immune cells on a single cell level infiltrating in the dermis at the injection site. Methods. AML patients, in first complete remission with measurable residual disease (MRD +) and not planned for HSCT at inclusion, received 4 biweekly doses of vididencel followed by 2 booster doses at week 14 and 18. Skin biopsies of the injection site were taken 2 days after the 1 st, 4 th and 6 th vaccination. Control samples were collected from unvaccinated/unaffected skin in two patients and from healthy controls. Samples were fixed and embedded in paraffin, and stained by standard immunohistochemistry for immune cell markers like CD4, CD8 and CD68 in the central lab. For patients treated at Haukeland University Hospital (N=6), tissue sections were prepared, mounted and stained with the panel of 29 antibodies labelled with heavy metal isotopes for use in the Hyperion mass cytometry imaging. For each sample a region of interest (ROI) of 2.8mm 2 was scanned based on the localization of the immune infiltrates, guided by standard H&E staining from neighboring slides. Results In 88.5% of patients injection site reactions were reported in this phase 2 study, characterized by redness, swelling and warmth at the site of intradermal injection, which were mild (maximum grade 1 or 2), and were of short duration (generally resolved within 12 days). Skin biopsies of a subset of 6 patients were analyzed using Hyperion. In standard single stain immunohistochemistry a large influx of CD4, CD8 and CD68 cells was observed in contrast to normal skin. Imaging mass cytometry confirmed these dense immune infiltrations. Using additional markers to characterize monocytes, dendritic cells and T-cells revealed that these cells are in close proximity and suggestive for cell-to-cell interaction (Figure 1). At sites of dense immune infiltration, influx of GranzymeB expressing CD8 T-cells and CD38 positive CD4 T-cells were observed as well as CD1c+ or CD141+ dendritic cells with high HLA-DR expression. These T-cells and dendritic cells are in close contact suggestive for patients' dendritic cells migrating from blood to skin, inducing a local immune response. Conclusion/discussion. Vaccination with vididencel triggered an inflammatory skin reaction in the majority of patients, with redness, warmth and swelling, of short duration, indicative for an active immune response at the site of injection. Skin biopsies using standard immunohistochemistry showed influx of activated CD4 and CD8 T cells as well as antigen presenting cell, including dendritic cells.Extended analysis with multiparameter imaging mass cytometry showed specific immune cell subsets infiltrating in these site of injection sites. The observed co-localization of the different immune subsets following vaccination supports the hypothesis of local antigen capturing by blood derived and local antigen presenting cells (Zuo et al, 2021). The local immune response may ultimately leads to a systemic immune response and disease control.

BCG infection dose guides dendritic cell migration and T cell priming in the draining lymph node.

In contrast to delayed-type hypersensitivity (DTH) and other hallmark reactions of cell-mediated immunity that correlate with vaccine-mediated protection against Mycobacterium tuberculosis, the contribution of vaccine dose on responses that emerge early after infection in the skin with Bacille Calmette-Guérin (BCG) is not well understood. We used a mouse model of BCG skin infection to study the effect of BCG dose on the relocation of skin Dendritic cells (DCs) to draining lymph node (DLN). Mycobacterium antigen 85B-specific CD4+ P25 T cell-receptor transgenic (P25 TCRTg) cells were used to probe priming to BCG in DLN. DC migration and T cell priming were studied across BCG inocula that varied up to 100-fold (104 to 106 Colony-forming units-CFUs). In line with earlier results in guinea pigs, DTH reaction in our model correlated with BCG dose. Importantly, priming of P25 TCRTg cells in DLN also escalated in a dose-dependent manner, peaking at day 6 after infection. Similar dose-escalation effects were seen for DC migration from infected skin and the accompanying transport of BCG to the DLN. BCG-triggered upregulation of co-stimulatory molecules on migratory DCs was restricted to the first 24 hour after infection and was independent of BCG dose over a 10-fold range (105 to 106 CFUs). The dose seemed to be a determinant of the number of total skin DCs that move to the DLN. In summary, our results support the use of higher BCG doses to detect robust DC migration and T cell priming.

Iontophoresis‐Driven Microneedle Arrays Delivering Transgenic Outer Membrane Vesicles in Program that Stimulates Transcutaneous Vaccination for Cancer Immunotherapy

Transdermal delivery of antigen and chemokine proteins that activates the maturation of skin dendritic cells (DCs) and direct the migration of activated DCs to lymph and spleen is an important alternative to conventional vaccines. However, stratum corneum forms a barrier to skin penetration. The poor cellular uptake of free antigens and chemokines also limits transcutaneous immunization efficacy. In this work, a pair of iontophoresis‐driven microneedle patches is constructed, of which, two kinds of outer membrane vesicles (OMVs) derived from Escherichia coli transformed by plasmid encoding gp100 (IPMN‐G) and chemokine ligand 21 (IPMN‐C) are incorporated within microneedles, respectively. The topical application of IPMN‐G and IPMN‐C shows the effectiveness of transdermally delivering gp100 and CCL21 secreting vesicles to skin DCs. With iontophoresis as a driving generator, the release and uptake of transgenic OMVs in target cells are significantly enhanced, with transcutaneous immunization initiated. The in vivo applications of IPMN‐G and IPMN‐C with a 12 h interval retard the progression and prevent the occurrence of tumor spheroids. IPMN‐GC is shown as a promising triplatform in engineering transgenic OMV‐incorporated microneedles, driven by iontophoresis into a transcutaneous vaccine, providing a noninvasive system for the transdermal delivery of antigen and chemokine proteins for transcutaneous vaccination‐meditated immunotherapy.

The Role of Sphingolipids and Sphingosine-1-phosphate-Sphingosine-1-phosphate-receptor Signaling in Psoriasis.

Psoriasis is a long-lasting skin condition characterized by redness and thick silver scales on the skin's surface. It involves various skin cells, including keratinocytes, dendritic cells, T lymphocytes, and neutrophils. The treatments for psoriasis range from topical to systemic therapies, but they only alleviate the symptoms and do not provide a fundamental cure. Moreover, systemic treatments have the disadvantage of suppressing the entire body's immune system. Therefore, a new treatment strategy with minimal impact on the immune system is required. Recent studies have shown that sphingolipid metabolites, particularly ceramide and sphingosine-1-phosphate (S1P), play a significant role in psoriasis. Specific S1P-S1P-receptor (S1PR) signaling pathways have been identified as crucial to psoriasis inflammation. Based on these findings, S1PR modulators have been investigated and have been found to improve psoriasis inflammation. This review will discuss the metabolic pathways of sphingolipids, the individual functions of these metabolites, and their potential as a new therapeutic approach to psoriasis.

Liposomes loaded with vitamin D3 induce regulatory circuits in human dendritic cells.

Nanomedicine provides a promising platform for manipulating dendritic cells (DCs) and the ensuing adaptive immune response. For the induction of regulatory responses, DCs can be targeted in vivo with nanoparticles incorporating tolerogenic adjuvants and auto-antigens or allergens. Here, we investigated the tolerogenic effect of different liposome formulations loaded with vitamin D3 (VD3). We extensively phenotyped monocyte-derived DCs (moDCs) and skin DCs and assessed DC-induced regulatory CD4+ T cells in coculture. Liposomal VD3 primed-moDCs induced the development of regulatory CD4+ T cells (Tregs) that inhibited bystander memory T cell proliferation. Induced Tregs were of the FoxP3+ CD127low phenotype, also expressing TIGIT. Additionally, liposome-VD3 primed moDCs inhibited the development of T helper 1 (Th1) and T helper 17 (Th17) cells. Skin injection of VD3 liposomes selectively stimulated the migration of CD14+ skin DCs. These results suggest that nanoparticulate VD3 is a tolerogenic tool for DC-mediated induction of regulatory T cell responses.

Androgen signaling shapes the sexual differences of skin immunity by regulating ILC2 and dendritic cells

Abstract The skin immune system mediates the skin health status, but the sex differences of the skin immune system are still unclear. This study aims to investigate sex differences in the skin immune system and decipher the underlying regulatory factors. We found that female mice have a higher magnitude of adaptive immune responses during commensal bacteria association and pathogen infection. Correspondingly, females have a higher level of skin dendritic cells (DCs), which play a fundamental role in commensal-induced adaptive immune responses. These sex differences were regulated by male sex hormones, that castration of males normalized the sex differences in the level of skin immune cells as well as the adaptive immune responses to bacteria. However, our scRNA-seq data reveals that androgen receptor is not expressed in DCs, but highly expressed in skin ILC2. Females have a significantly higher level of ILC2 than males and ILC2 from females also have a more activating gene expression signature than ILC2 from males. Females also have a significantly higher level of ILC2-produced IL-13 and GM-CSF than male mice. In addition, our data reveal that IL-13 and GM-CSF play a critical role to maintain the level of skin DCs, that IL-13/GM-CSF deficient mice have a remarkable decrease of skin DCs, and the sex differences of DCs are also largely impaired. Therefore, based on these findings, we suggest that androgen signaling negatively regulates the level of skin ILC2 and DCs, thereby shaping sex-specific skin immunity to commensals, pathogens, and/or other stimuli. Collectively our work proposes a mechanism for the heighten immunity observed in female and have important implication for our understanding of tissue immunity in the context of infection and cancer.

Adaptive immunity to ancient retroelements controls the skin tissue threshold of activation

Abstract A symbiotic dialogue between the microbiota and host is essential to promote protective immune responses in the skin. Integrated retroviral elements, or retrotransposons (RTNs), comprise up to 45% of the human genome. We previously found that immune responses to the skin microbiota are dependent on the reactivation and keratinocyte-intrinsic sensing of RTNs. Here, we explored the possibility that RTNs may also represent a source of antigens recognized by the skin adaptive immune system. We first established a model of sterile injury, where topical application of a mild detergent reactivated RTNs, and recruited CD8 T cells to the skin in an RTN-dependent manner. RNAseq analysis of RTN expression revealed Langerhans cells (LCs) have the most abundant RTN expression amongst skin dendritic cells. Our work demonstrated that CD8 T cell responses to sterile injury were entirely dependent on LCs, supporting the idea that LCs could present RTN antigens to CD8 T cells. To identify RTN-specific T cells, we selected peptides that were uniquely expressed in LCs, but not in thymic epithelial cells which mediate negative selection. Several peptides promoted cytokine production from injury-elicited CD8 T cells, confirming the presence of RTN-reactive CD8 T cells in the skin. RNA-seq analysis suggests RTN-specific CD8 T cells may contribute to wound repair and immunoregulation. Thus, mild stress, such as that induced by mild detergent, is sufficient to promote adaptive immunity to defined antigens derived from RTNs. Our work also proposes that homeostatic immunity to ancient retroviruses promotes a defined class of T cells responses aimed at maintaining barrier integrity in response to daily stressors encountered by the skin. Cancer Research Institute, Irvington Postdoctoral Fellowship

172 Spatiotemporal architecting of skin dendritic cell directed immunity and tolerance

172 Spatiotemporal architecting of skin dendritic cell directed immunity and tolerance

Molecular Mechanisms of Neurogenic Inflammation of the Skin.

The skin, including the hypodermis, is the largest body organ and is in constant contact with the environment. Neurogenic inflammation is the result of the activity of nerve endings and mediators (neuropeptides secreted by nerve endings in the development of the inflammatory reaction in the skin), as well as interactions with other cells such as keratinocytes, Langerhans cells, endothelial cells and mast cells. The activation of TRPV-ion channels results in an increase in calcitonin gene-related peptide (CGRP) and substance P, induces the release of other pro-inflammatory mediators and contributes to the maintenance of cutaneous neurogenic inflammation (CNI) in diseases such as psoriasis, atopic dermatitis, prurigo and rosacea. Immune cells present in the skin (mononuclear cells, dendritic cells and mast cells) also express TRPV1, and their activation directly affects their function. The activation of TRPV1 channels mediates communication between sensory nerve endings and skin immune cells, increasing the release of inflammatory mediators (cytokines and neuropeptides). Understanding the molecular mechanisms underlying the generation, activation and modulation of neuropeptide and neurotransmitter receptors in cutaneous cells can aid in the development of effective treatments for inflammatory skin disorders.

Pseudomonas aeruginosa LecB suppresses immune responses by inhibiting transendothelial migration.

Pseudomonas aeruginosa is a Gram-negative bacterium causing morbidity and mortality in immuno-compromised humans. It produces a lectin, LecB, that is considered a major virulence factor, however, its impact on the immune system remains incompletely understood. Here we show that LecB binds to endothelial cells in human skin and mice and disrupts the transendothelial passage of leukocytes in vitro. It impairs the migration of dendritic cells into the paracortex of lymph nodes leading to a reduced antigen-specific T cell response. Under the effect of the lectin, endothelial cells undergo profound cellular changes resulting in endocytosis and degradation of the junctional protein VE-cadherin, formation of an actin rim, and arrested cell motility. This likely negatively impacts the capacity of endothelial cells to respond to extracellular stimuli and to generate the intercellular gaps for allowing leukocyte diapedesis. A LecB inhibitor can restore dendritic cell migration and T cell activation, underlining the importance of LecB antagonism to reactivate the immune response against P.aeruginosa infection.

In-silico Characterization of Target Protein in Dengue Infection

Infection of humans with the virus is primarily mediated by the Aedes mosquito. The virus grows in the mosquito gut and migrates to aq 1 the salivary glands.. Dengue virus (DENV), which includes four serotypes (DENV1–4), is transmitted to humans by Aedes mosquitos and is the etiological agent of dengue fever and dengue hemorrhagic fever. DENV causes an estimated 50–100 million cases of dengue fever, 500,000 cases of severe dengue (dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS)), and more than 20,000 deaths each year in tropical and subtropical regions, representing a considerable public health threat in over 100 countries worldwide. However, there are still no specific antiviral drugs or licensed vaccines against DENV infection. Dengue virus primarily propagates in skin dendritic cells, and subsequently virus proliferation is thought to occur in target cells such as those of the monocyte/macrophage lineage. Second, carbohydrate binding proteins, termed lectins, expressed on dendritic cells (DCs) and macrophages under the human skin are involved in initial contact of DENV introduced by mosquito bite. Among these lectins, dendritic cell-specific intercellular adhesion molecule-3-grabbing non integrin (DCSIGN) has been best characterized in virus-DC interaction.

Topical Application of Adenosine A2-Type Receptor Agonists Prevents Contact Hypersensitivity Reactions in Mice by Affecting Skin Dendritic Cells

Adenosine (Ado) produced by skin and skin migratory CD73+ dendritic cells is critically involved in tolerance tohaptens. We therefore investigated the use of Ado receptor agonists for the treatment of contact hypersensitivity reactions. A2A- 4-[2-[[6-Amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino] ethyl]benzenepropanoic acid hydrochloride (CGS) and A2B- 2-[[6-Amino-3,5-dicyano-4-[4-[cyclopropylmethoxy]phenyl]-2-pyridinyl]thio]-acetamide (BAY) specific Ado receptor agonists were epicutaneously applied to the skin before sensitization and challenge with DNFB. Both agonists reduced ear swelling compared with solvent controls. This was accompanied by fewer activated T cells in the skin after the challenge and by higher numbers of T cells expressing anergic markers such as LAG-3, CD137, PD-1, CD272, and TIM-3 in the lymph nodes of CGS-treated groups. In ear tissue, Ado receptor agonist treatment reduced the production of proinflammatory cytokines and chemokines as well as the infiltration by neutrophils after sensitization. Moreover, reduced numbers of skin migratory dendritic cells producing less IL-12 and exhibiting lower expression of CD86 were recorded in lymph nodes after sensitization. In cocultures of skin migratory dendritic cells from CGS-treated mice with T cells, reduced proliferation of T cells and decreased secretion of proinflammatory cytokines compared with that of solvent controls were apparent. In conclusion, topical application of Ado receptor agonists to the skin prevents sensitization of T cells against haptens by reducing the migration and activation of skin migratory dendritic cells.

433 Loricrin imprints adaptive immunity

Langerhans cells (LCs) are skin dendritic cells (DCs) that communicate with epidermal keratinocytes (KCs) and activate endogenous transforming growth factor-beta (TGF-β) signaling. Loricrin provides the stratum corneum (SC) with force resistance through promoting disulfide-mediated cross-linkages of keratins and desmosomes, and structural maturation of the desmosome-keratin scaffold has previously been shown to be hampered in the SC of loricrin-knockout (LKO) mice. We suspected that LOR might promote the maturation of the actin-anchored apical junctional complex (adherence/tight junctions) and integrins, the latter of which is a prerequisite for the retention of epidermal LCs.