Abstract Conventional dendritic cell (cDC1, cDC2) and plasmacytoid dendritic cell (pDCs) subsets have specialized functions that can be modulated by the tumor microenvironment (TME). These cells produce different interferons that are central to antitumor immune responses. While the role of Type I Interferons (IFN-I) in tumor immunity is well characterized, the role of Type III interferons (IFN-III) produced by cDC1 in the TME which is associated with good outcome remains completely unknown. Here, we demonstrate that IFN-III orchestrates pDCs survival, activation and TLR7 expression in the blood and in tumors, enhancing their capacity to respond to TLR7-ligand. Importantly, IFN-III prevents the inhibition of pDCs induced by the TME or by TGF-β, a dominant TME inhibitory cue, and restores their production of IFN-α. Because of the essential role of TGF-β in immune regulation, this mechanism is expected to impact other pathological situations.

BackgroundEpicutaneous immunotherapy (EPIT) protocols have recently been developed to restore tolerance in patients with food allergy. The mechanisms by which EPIT protocols promote desensitization rely on a profound immune deviation of pathogenic T- and B-cell responses.ObjectiveTo date, little is known about the contribution of skin dendritic cells (skDCs) to T-cell remodeling and EPIT efficacy.MethodsWe capitalized on a preclinical model of food allergy to ovalbumin (OVA) to characterize the phenotype and functions of OVA+ skDCs throughout the course of EPIT.ResultsOur results showed that both Langerhans cells and dermal conventional cDC1 and cDC2 subsets retained their ability to capture OVA in the skin and to migrate toward the skin-draining lymph nodes during EPIT. However, their activation/maturation status was significantly impaired, as evidenced by the gradual and selective reduction of CD86, CD40, and OVA protein expression in respective subsets. Phenotypic changes during EPIT were also characterized by a progressive diversification of single-cell gene signatures within each DC subset. Interestingly, we observed that OVA+ Langerhans cells progressively lost their capacity to prime CD4+ TEFF cells, but gained regulatory T-cell stimulatory properties. In contrast, cDC1 were inefficient in priming CD4+ TEFF cells or in reactivating TMEM cells in vitro, whereas cDC2 retained moderate stimulatory properties, and progressively biased type 2 immunity toward type 1 and type 17 responses.ConclusionsOur results therefore emphasize that the acquisition of distinct phenotypic and functional specializations by skDCs during EPIT is at the cornerstone of the desensitization process.

Recent studies demonstrated that a key activator of TGF-β, integrin αvβ8, is highly expressed on migrating intestinal dendritic cells, resulting in enhanced induction of Tregs. The aim of this study was to evaluate the expression of integrin αvβ8 on different populations of skin DCs and their role in Tregs induction in sensitized mice during EPIT. OVA-sensitized BALB/c mice were treated for 48hrs with a patch containing OVA-A647. Phenotypes of OVA+ migrating Langerhans cells (mig-LCs) and CD11b+ dDCs (mig-cDC2s) in draining lymph nodes were evaluated by flow cytometry, and their capacity to induce Tregs in vitro was measured in co-culture experiments. In vivo induction of Tregs was evaluated in OVA-sensitized LANG-eGFP-DTR mice in the presence or absence of LCs. After 48hrs application, OVA+ mig-LCs and OVA+ mig-cDC2s showed increased expression of integrin αv (median of mfi 630 [466-996] and 1105 [973-1597] respectively) compared to OVAneg corresponding cells (261 [227-285] and 372 [305-396] respectively) (p<0.01). OVA+ mig-LCs expressed significantly higher levels of integrin β8 compared to OVA- mig-LCs (4281 [2949-8619] vs 1633 [1448-2541] respectively) (p<0.05). In vitro, LCs induced significantly higher levels of CD62L+ Foxp3+(72.6% [71.8-77.9] vs 41.2%[35.6-44.4]) and LAPhi Tregs (1.91% of CD4+ [1.76-2.19] vs 0.37%[0.01-0.61]) compared to cDC2s (p<0.05). In vivo, induction of CD62L+Foxp3+, and LAP+ Tregs by EPIT was not observed in the absence of Langerhans cells. The preferential expression of integrin αvβ8 by LCs and their essential role in Tregs induction strongly suggest a role of the TFG-β pathway in the mechanism of induction of tolerance by EPIT.

The human skin is known to be inhabited by diverse microbes, including bacteria, fungi, viruses, archaea, and mites. This microbiome exerts a protective role against infections by promoting immune development and inhibiting pathogenic microbes to colonize skin. One of the factors having an intense effect on the skin and its resident microbes is ultraviolet-radiation (UV-R). UV-R can promote or inhibit the growth of microbes on the skin and modulate the immune system which can be either favorable or harmful. Among potential UV-R targets, skin resident memory T cells (TRM) stand as well positioned immune cells at the forefront within the skin. Both CD4+ or CD8+ αβ TRM cells residing permanently in peripheral tissues have been shown to play prominent roles in providing accelerated and long-lived specific immunity, tissue homeostasis, wound repair. Nevertheless, their response upon UV-R exposure or signals from microbiome are poorly understood compared to resident TCRγδ cells. Skin TRM survive for long periods of time and are exposed to innumerable antigens during lifetime. The interplay of TRM with skin residing microbes may be crucial in pathophysiology of various diseases including psoriasis, atopic dermatitis and polymorphic light eruption. In this article, we share our perspective about how UV-R may directly shape the persistence, phenotype, specificity, and function of skin TRM; and moreover, whether UV-R alters barrier function, leading to microbial-specific skin TRM, disrupting the healthy balance between skin microbiome and skin immune cells, and resulting in chronic inflammation and diseased skin.

Immune-mediated skin diseases induced by chemicals and drugs are mainly T-cell mediated reactions, i.e. type IV hypersensitivity of the Gell & Coombs classification. Clinical expressions depend on the exposition route of the chemical with allergic contact dermatitis in case of skin exposure and delayed drug allergy in case of oral or parenteral intake. Allergic contact dermatitis and delayed drug allergy share common pathophysiologic pathways with chemical-specific T cells recruitment to the skin to eliminate chemical-expressing keratinocytes. In this review, we discuss the pathophysiology of allergic contact dermatitis and delayed drug allergy with focus on their common pathways.

The skin is a major immunologic organ that may induce protection, sensitization or tolerance. Epicutaneous immunotherapy (EPIT) has been proposed as an attractive strategy to actively treat food allergy and has been shown to induce tolerance in sensitized mice through the induction of Foxp3(+) regulatory T cells (Tregs), especially CD62L(+) Tregs. Among immune cells in the skin, dendritic cells are key players in antigen-specific immune activation or regulation. The role of different populations of skin DCs in tolerance induction remains to be elucidated. Using OVA-sensitized BALB/c mice, we demonstrated that the application of a patch containing OVA-A647 to the skin resulted in allergen uptake by Langerhans cells (LCs) and CD11b(+) dermal cDC2 and subsequent migration into skin draining lymph nodes. These 2 populations induced Foxp3 expression in CD4(+) cells in vitro. Only LCs induced LAP(+) cells and CD62L(+) Tregs. Using Langerin-eGFP-DTR mice, we analyzed the role of LCs in the mechanisms of tolerance induction by EPIT in vivo. Following complete depletion of LCs, a dramatic decrease in the number of OVA(+) DCs and OVA(+) CD11b(+) dermal cDC2 was observed in skin draining lymph nodes 48 h after epicutaneous application. Likewise, 2 weeks of EPIT in non-depleted mice induced Foxp3(+) Tregs, especially CD62L(+), and LAP(+) Tregs in skin draining lymph nodes and spleen, whereas no induction of Tregs was observed in LC-depleted mice. Following 8 weeks of treatment, EPIT-treated mice showed significant protection against anaphylaxis accompanied by a significant increase of Foxp3(+) Tregs, especially CD62L(+) Tregs, which was not seen in the absence of LCs. In summary, although both LCs and CD11b(+) dermal cDC2s could induce regulatory T cells, the absence of LCs during EPIT impaired treatment efficacy, indicating their crucial role in skin-induced tolerance.

Atopic dermatitis (AD) is a common skin inflammatory disease characterized by the production of thymic stromal lymphopoietin (TSLP) and marked TH 2 polarization. Recent studies suggest that IL-1β contributes to the development of AD skin inflammation. Here, we have investigated the impact of IL-1β signalling on the epidermal homeostasis of both healthy subjects and AD patients [with functional filaggrin (FLG) alleles], with particular attention to TSLP production and keratinocyte differentiation. In healthy reconstructed human epidermis (RHE), IL-1β promoted (i) robust secretion of TSLP in an NF-κB-dependent manner and (ii) a significant decrease in the expression of filaggrin and other proteins of the epidermal differentiation complex. These effects were prevented by treatment of RHE with the anti-IL-1β mAb canakinumab and by the IL-1 receptor antagonist anakinra. Interestingly, RHE generated from AD donors behaved like that of healthy individuals and showed comparable responses to IL-1β signals. Collectively, our results suggest that IL-1β may be an early key mediator for the acquisition of an AD phenotype through induction of TSLP and alteration of the epidermal homeostasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Introduction Les lymphocytes T mémoires résidents (TRM) sont des lymphocytes T mémoires qui persistent à long terme dans les tissus périphériques tels que la peau sans recirculer dans l’organisme. Bien que ces cellules assurent une surveillance immunitaire efficace contre les pathogènes, elles peuvent potentiellement aggraver de nombreuses maladies inflammatoires comme les allergies cutanées. Matériel et méthodes Dans cette étude, nous avons analysé la persistance de TRM dans les lésions guéries et leur contribution aux récidives et à la sévérité de l’eczéma allergique de contact. Pour ce faire, nous avons utilisé un modèle murin d’hypersensibilité retardée de contact (HSRC) induit par un haptène fort : le 2,4-dinitrofluorobenzène (DNFB). Résultats Nos résultats montrent qu’un nombre important de lymphocytes T CD8+, exprimant des marqueurs canoniques de TRM, tels que CD103 et CD69, persistent dans l’épiderme et le derme des lésions antérieures (en comparaison de la peau non atteinte), plus de 30jours après la résolution de la réaction d’eczéma. Approximativement 2 % de ces TRM sont spécifiques du DNFB et produisent de l’interféron (IFN)-g après restimulation ex vivo. Ces cellules sont responsables de récidives plus sévères observées sur les sites de lésion antérieure. De manière surprenante, malgré leur position stratégique au sein du tissu, les TRM sont incapables d’induire une inflammation suite à une exposition répétée à de faibles doses d’haptène, suggérant une régulation fine de l’activation de ces cellules dans le tissu. En ce sens, nous avons observé que les TRM de la peau expriment plusieurs récepteurs de co-stimulation négative (PD1-1, TIM-3, CD244) et que bloquer ces récepteurs en utilisant des anticorps monoclonaux augmentent leur réactivation ex vivo. Nos travaux en cours visent à développer des stratégies ciblant ces récepteurs de co-stimulation négatif afin de limiter la réactivation de ces TRM cutanés in situ et restaurer une tolérance chez les individus allergiques.