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Skin-resident mast cells (MCs) and cutaneous sensory neurons both play crucial roles in microbial‒host defense and inflammatory diseases. MCs can be directly activated by pathogens or their products, resulting in the release of numerous mediators that promote innate immune responses and also activate sensory neurons. Cutaneous sensory neurons can also directly detect the presence of pathogens, resulting in the release of neuropeptides that modulate MC function. In this review, we will focus on the reciprocal interactions between cutaneous sensory neurons and MCs and the importance of this cross-talk in skin diseases.

The cytokine interleukin-23 (IL-23) is critical for development and maintenance of autoimmune inflammation in nonlymphoid tissues; however, the mechanism through which IL-23 supports tissue-specific immunity remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from Candida albicans skin infection, and tissue-resident memory (T RM ) cell–mediated protection from C. albicans reinfection required IL-23. Administration of anti–IL-23 receptor antibody to mice after resolution of primary C. albicans infection resulted in loss of CD69 + CD103 + tissue-resident memory T helper 17 (T RM17 ) cells from skin, and clinical anti–IL-23 therapy depleted T RM17 cells from skin of patients with psoriasis. IL-23 receptor blockade impaired T RM17 cell proliferation but did not affect apoptosis susceptibility or tissue egress. IL-23 produced by CD301b + myeloid cells was required for T RM17 maintenance in skin after C. albicans infection, and CD301b + cells were necessary for T RM17 expansion during the development of imiquimod dermatitis. This study demonstrates that locally produced IL-23 promotes in situ proliferation of cutaneous T RM17 cells to support their longevity and function and provides mechanistic insight into the durable efficacy of IL-23 blockade in the treatment of psoriasis.

Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the United States population. This guideline addresses important clinical questions that arise in psoriasis management and care and provides recommendations based on the available evidence. The treatment of psoriasis with topical agents and with alternative medicine will be reviewed, emphasizing treatment recommendations and the role of dermatologists in monitoring and educating patients regarding benefits as well as risks that may be associated. This guideline will also address the severity assessment methods of psoriasis in adults.

Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 2% of the world's population. In this guideline, we focus the discussion on systemic, nonbiologic medications for the treatment of this disease. We provide detailed discussion of efficacy and safety for the most commonly used medications, including methotrexate, cyclosporine, and acitretin, and provide recommendations to assist prescribers in initiating and managing patients on these treatments. Additionally, we discuss newer therapies, including tofacitinib and apremilast, and briefly touch on a number of other medications, including fumaric acid esters (used outside the United States) and therapies that are no longer widely used for the treatment of psoriasis (ie, hydroxyurea, leflunomide, mycophenolate mofetil, thioguanine, and tacrolimus).

CD8+ memory T cells provide anamnestic host defense against intracellular pathogens and cancer immunosurveillance but are also pathogenic in some autoimmune diseases. In mouse skin, there are two unique subsets of CD8+ memory T cells, resident memory cells that reside long-term in steady state skin and recirculating memory cells that are transient. They have distinct mechanisms of recruitment, development, and maintenance in response to skin-derived signals. In this review, we will focus on these mechanisms and the functional relationship of these two types of CD8+ memory cells with host defense and disease.

The skin is innervated by numerous sensory afferent neurons that respond to a diverse array of stimuli ranging from gentle touch to noxious pain. Various features of the immune system—pathogen recognition, secretion of soluble mediators—are shared with the nervous system. This has led to the recognition that neurons share some functions with innate immune cells and have the capacity to recognize pathogens and participate in innate immune responses. Neuroimmune interactions are bidirectional. Soluble mediators from immune cells activate neurons and soluble mediators from neurons can activate immune cells. In this review, we will focus on the interplay between neurons and innate immunity in the skin in the context of host defense and inflammation.

Psoriasis is a chronic, multisystem, inflammatory disease that affects approximately 1% of children, with onset most common during adolescence. This guideline addresses important clinical questions that arise in psoriasis management and provides evidence-based recommendations. Attention will be given to pediatric patients with psoriasis, recognizing the unique physiology, pharmacokinetics, and patient-parent-provider interactions of patients younger than 18 years old. The topics reviewed here mirror those discussed in the adult guideline sections, excluding those topics that are irrelevant to, or lack sufficient information for, pediatric patients.

Psoriasis is a chronic inflammatory disease involving multiple organ systems and affecting approximately 3.2% of the world's population. In this section of the guidelines of care for psoriasis, we will focus the discussion on ultraviolet (UV) light-based therapies, which include narrowband and broadband UVB, UVA in conjunction with photosensitizing agents, targeted UVB treatments such as with an excimer laser, and several other modalities and variations of these core phototherapies, including newer applications of pulsed dye lasers, intense pulse light, and light-emitting electrodes. We will provide an in-depth, evidence-based discussion of efficacy and safety for each treatment modality and provide recommendations and guidance for the use of these therapies alone or in conjunction with other topical and/or systemic psoriasis treatments.

BACKGROUND: Allergic contact dermatitis (CD) is a chronic inflammatory skin disease caused by type-1 biased adaptive immunity for which there is an unmet need for antigen (Ag)-specific immunotherapies. Exposure to skin sensitizers stimulates secretion of the proinflammatory neuropeptides substance P (SP) and hemokinin 1 (HK1), which signal via the neurokinin-1 receptor (NK1R) to promote the innate and adaptive immune responses of CD. Accordingly, mice lacking the NK1R develop impaired CD. Nonetheless, the role and therapeutic opportunities of targeting the NK1R in CD remain to be elucidated. OBJECTIVE: To develop an Ag-specific immunosuppressive approach to treat CD by skin co-delivery of hapten and NK1R antagonists integrated in dissolvable microneedle arrays (MNA). METHODS: In vivo mouse models of contact hypersensitivity and ex-vivo models of human skin were used to delineate the effects and mechanisms of NK1R-signaling and the immunosuppressive effects of the contact sensitizer-NK1R-antagonists-MNA in CD. RESULTS: We demonstrate in mice that CD requires NK1R signaling by SP and HK1. Specific deletion of the NK1R in keratinocytes and dendritic cells, but not in mast cells prevented CD. Skin co-delivery of hapten- or Ag-NK1R-antagonist-MNA inhibited neuropeptide-mediated skin inflammation in mouse and human skin, promoted deletion of Ag-specific effector T cells and increased regulatory T cells, which prevented CD onset and relapses locally and systemically in an Ag-specific manner. CONCLUSIONS: Our findings demonstrate that immune-regulation by engineering localized skin neuroimmune networks can be used to treat cutaneous diseases that like CD, are caused by type-1 immunity.

In the skin, Langerhans cells (LCs) require autocrine latent TGFβ that is transactivated by the integrins ανβ6 and ανβ8 expressed by keratinocytes (KCs) for long-term epidermal retention. Selective expression of a ligand-independent, constitutively active form of TGFβR1 inhibits LC migration during homeostasis and in response to UVB exposure. In this study, we found that LC migration in response to inflammatory stimuli was also inhibited by ligand-independent TGFβR1 signaling. Contrary to UVB stimulation, which reduced KC expression of ανβ6, invitro and invivo exposure to TNF-α or IL-1β increased ανβ6 transcript and protein expression by KCs. This resulted in increased KC-mediated transactivation of latent TGFβ. Expression of ανβ8 was largely unchanged. These findings show that ligand-independent TGFβR1 signaling in LCs can overcome inflammatory migration stimuli, but reduced KC-mediated transactivation of latent TGFβ by KCs may only drive LC migration during homeostasis and in response to UV stimulation.

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Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103+ gut dendritic cells (DCs), yet their role in commensal-reactive pTreg development is unclear. Using two Helicobacter-specific T cell receptor (TCR) transgenic mouse lines, we found that both CD103+ and CD103– migratory, but not resident, DCs from the colon-draining mesenteric lymph node presented Helicobacter antigens to T cells ex vivo. Loss of most CD103+ migratory DCs in vivo using murine genetic models did not affect the frequency of Helicobacter-specific pTreg cell generation or induce compensatory tolerogenic changes in the remaining CD103– DCs. By contrast, activation in a Th1-promoting niche in vivo blocked Helicobacter-specific pTreg generation. Thus, these data suggest a model where DC-mediated effector T cell differentiation is ‘dominant’, necessitating that all DC subsets presenting antigen are permissive for pTreg cell induction to maintain gut tolerance.

Summary Inflammatory response heterogeneity has impeded high-resolution dissection of diverse immune cell populations during activation. We characterize mouse cutaneous immune cells by single-cell RNA sequencing, after inducing inflammation using imiquimod and oxazolone dermatitis models. We identify 13 CD45+ subpopulations, which broadly represent most functionally characterized immune cell types. Oxazolone pervasively upregulates Jak2/Stat3 expression across T cells and antigen-presenting cells (APCs). Oxazolone also induces Il4/Il13 expression in newly infiltrating basophils, and Il4ra and Ccl24, most prominently in APCs. In contrast, imiquimod broadly upregulates Il17/Il22 and Ccl4/Ccl5. A comparative analysis of single-cell inflammatory transcriptional responses reveals that APC response to oxazolone is tightly restricted by cell identity, whereas imiquimod enforces shared programs on multiple APC populations in parallel. These global molecular patterns not only contrast immune responses on a systems level but also suggest that the mechanisms of new sources of inflammation can eventually be deduced by comparison to known signatures., Graphical Abstract, Highlights • Oxazolone pervasively upregulates Jak2/Stat3 expression across T cells and APCs • Il4/Il13 induction in skin by oxazolone is dominated by infiltrating basophils • Imiquimod broadly increases Il17/Il22 and Ccl4/Ccl5, extending to non-T cells • Oxazolone induces more highly compartmentalized immune cell responses than imiquimod, Immunology; Systems Biology

Background Atopic dermatitis (AD) is among the most common chronic inflammatory skin diseases, usually occurring early in life, and often preceding other atopic diseases such as asthma. TH2 has been believed to play a crucial role in cellular and humoral response in AD, but accumulating evidence has shown that follicular helper T cell (TFH), a critical player in humoral immunity, is associated with disease severity and plays an important role in AD pathogenesis. Objectives This study aimed at investigating how TFHs are generated during the pathogenesis of AD, particularly what is the role of keratinocyte-derived cytokine TSLP and Langerhans cells (LCs). Methods Two experimental AD mouse models were employed: (1) triggered by the overproduction of TSLP through topical application of MC903, and (2) induced by epicutaneous allergen ovalbumin (OVA) sensitization. Results This study demonstrated that the development of TFHs and germinal center (GC) response were crucially dependent on TSLP in both the MC903 model and the OVA sensitization model. Moreover, we found that LCs promoted TFH differentiation and GC response in the MC903 model, and the depletion of Langerin+ dendritic cells (DCs) or selective depletion of LCs diminished the TFH/GC response. By contrast, in the model with OVA sensitization, LCs inhibited TFH/GC response and suppressed TH2 skin inflammation and the subsequent asthma. Transcriptomic analysis of Langerin+ and Langerin− migratory DCs revealed that Langerin+ DCs became activated in the MC903 model, whereas these cells remained inactivated in OVA sensitization model. Conclusions Together, these studies revealed a dual functionality of LCs in TSLP-promoted TFH and TH2 differentiation in AD pathogenesis.

Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus Candida albicans. IL-17R signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F, and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this “experiment of nature” by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9. Unlike Il17f−/− mice that are resistant to OPC, Il17fS65L/S65L mice showed increased oral fungal burdens similar to Il17a−/− mice. In contrast to humans, however, disease was only evident in homozygous, not heterozygous, mutant mice. The mutation was linked to modestly impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in oral antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi. Moreover, because these mice do not phenocopy Il17f−/− mice, they may provide a valuable tool to interrogate IL-17F and IL-17AF function in vivo in other settings.

Atopic dermatitis (AD) is among the most common chronic inflammatory skin diseases, usually occurring early in life, and often preceding other atopic diseases such as asthma. TThis study aimed at investigating how TTwo experimental AD mouse models were employed: (1) triggered by the overproduction of TSLP through topical application of MC903, and (2) induced by epicutaneous allergen ovalbumin (OVA) sensitization.This study demonstrated that the development of TTogether, these studies revealed a dual functionality of LCs in TSLP-promoted T

Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungusC. albicans. IL-17 receptor signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this ‘experiment of nature’ by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9.The resultingIl17fS65L/S65Lmice showed increased susceptibility to OPC, but only in homozygous, not heterozygous, mutant mice. The mutation was linked to impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi.

Intestinal microbes release ATP to modulate local immune responses. Herein we demonstrates that Candida albicans, an opportunistic commensal fungus, also modulates immune responses via secretion of ATP. We found that ATP secretion from C. albicans varied between standard laboratory strains. A survey of eighty-nine clinical isolates revealed heterogeneity in ATP secretion, independent of growth kinetics and intracellular ATP levels. Isolates from blood released less ATP than commensals, suggesting that ATP secretion assists with commensalism. To confirm this, cohorts of mice were infected with strains matched for origin, and intracellular ATP concentration, but high or low extracellular ATP. In all cases fungal burden was inversely correlated with ATP secretion. Mice lacking P2RX7, the key ATP receptor expressed by immune cells in the skin, showed no alteration in fungal burden. Rather, treatments with a P2RX2/3 antagonist result in increased fungal burden. P2RX2/3 is expressed by non-peptidergic neurons that terminate in the epidermis. Cultured sensory neurons flux Ca2+ when exposed to supernatant from heat-killed C. albicans (HKCA), and these non-peptidergic fibers are the dominant subset that respond to HKCA. Ca2+ flux, but not CGRP-release, can be abrogated by pretreatment of HKCA supernatant with apyrase. To determine whether non-peptidergic neurons participate in host defense, we generated MRGPRD-DTR mice. Infection in these mice resulted in increased CFU only for those C. albicans strains with high ATP secretion. Taken together, our findings indicate that C. albicans releases ATP, which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses.Author SummaryBacterial release of ATP has been shown to modulate immune responses. Candida albicans displays heterogeneity in ATP release among laboratory strains and commensal clinical isolates release more ATP than invasive isolates. C. albicans strains with high ATP secretion show lower fungal burden following epicutaneous infection. Mice lacking P2RX7, the key ATP receptor expressed by immune cells, showed no alteration in fungal burden. In contrast, treatment with P2RX2/3 antagonists resulted in increased fungal burden. P2RX3 is expressed by a subset of non-peptidergic neurons that terminate in the epidermis. These non-peptidergic fibers are the predominant responders when cultured sensory neurons are exposed to heat-killed C. albicans in vitro. Mice lacking non-peptidergic neurons have increased infection when exposed to high but not low ATP-secreting isolates of C. albicans. Taken together, our findings indicate that C. albicans releases ATP which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses.Bullet pointsATP released from heat killed C. albicans activates non-peptidergic sensory neuronsLive C. albicans clinical isolates release variable amounts of ATPElevated levels of ATP released by C. albicans correlates with reduced infectivity in vivoMRGPRD-expressing cutaneous neurons are required for defense against ATP-secreting C. albicans

Effective subunit vaccines require the incorporation of adjuvants that stimulate cells of the innate immune system to generate protective adaptive immune responses. Pattern recognition receptor agonists are a growing class of potential adjuvants that can shape the character of the immune response to subunit vaccines by directing the polarization of CD4 T cell differentiation to various functional subsets. In the current study, we applied a high-throughput in vitro screen to assess murine CD4 T cell polarization by a panel of pattern recognition receptor agonists. This identified lipopeptides with TLR2 agonist activity as exceptional Th1-polarizing adjuvants. In vivo, we demonstrated that i.v. administration of TLR2 agonists with Ag in mice replicated the findings from in vitro screening by promoting strong Th1 polarization. In contrast, TLR2 agonists inhibited priming of Th1 responses when administered cutaneously in mice. This route-specific suppression was associated with infiltrating CCR2+ cells in the skin-draining lymph nodes and was not uniquely dependent on any of the well characterized subsets of dendritic cells known to reside in the skin. We further demonstrated that priming of CD4 T cells to generate Th1 effectors following immunization with the Mycobacterium bovis bacillus Calmette–Guérin (BCG) strain, a lipoprotein-rich bacterium recognized by TLR2, was dependent on the immunization route, with significantly greater Th1 responses with i.v. compared with intradermal administration of BCG. A more complete understanding of route-dependent TLR2 responses may be critical for informed design of novel subunit vaccines and for improvement of BCG and other vaccines based on live-attenuated organisms.

The skin provides both a physical barrier and an immunologic barrier to external threats. The protective machinery of the skin has evolved to provide situation-specific responses to eliminate pathogens and to provide protection against physical dangers. Dysregulation of this machinery can give rise to the initiation and propagation of inflammatory loops in the epithelial microenvironment that result in inflammatory skin diseases in susceptible people. A defective barrier and microbial dysbiosis drive an interleukin 4 (IL-4) loop that underlies atopic dermatitis, while in psoriasis, disordered keratinocyte signaling and predisposition to type 17 responses drive a pathogenic IL-17 loop. Here we discuss the pathogenesis of atopic dermatitis and psoriasis in terms of the epithelial immune microenvironment-the microbiota, keratinocytes and sensory nerves-and the resulting inflammatory loops.

Professional antigen-presenting cells (APCs) in the skin include dendritic cells, monocytes, and macrophages. They are highly dynamic, with the capacity to enter skin from the peripheral circulation, patrol within tissue, and migrate through lymphatics to draining lymph nodes. Skin APCs are endowed with antigen-sensing, -processing, and -presenting machinery and play key roles in initiating, modulating, and resolving cutaneous inflammation. Skin APCs are a highly heterogeneous population with functionally specialized subsets that are developmentally imprinted and modulated by local tissue microenvironmental and inflammatory cues. This review explores recent advances that have allowed for a more accurate taxonomy of APC subsets found in both mouse and human skin. It also examines the functional specificity of individual APC subsets and their collaboration with other immune cell types that together promote adaptive T cell and regional cutaneous immune responses during homeostasis, inflammation, and disease.

Cutaneous mast cells mediate numerous skin inflammatory processes and have anatomical and functional associations with sensory afferent neurons. We reveal that epidermal nerve endings from a subset of sensory nonpeptidergic neurons expressing MrgprD are reduced by the absence of Langerhans cells. Loss of epidermal innervation or ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, including the activating receptor, Mrgprb2, resulting in increased mast cell degranulation and cutaneous inflammation in multiple disease models. Agonism of MrgprD-expressing neurons reduced expression of module genes and suppressed mast cell responses. MrgprD-expressing neurons released glutamate which was increased by MrgprD agonism. Inhibiting glutamate release or glutamate receptor binding yielded hyperresponsive mast cells with a genomic state similar to that in mice lacking MrgprD-expressing neurons. These data demonstrate that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release, thereby revealing an unexpected neuroimmune mechanism maintaining cutaneous immune homeostasis.

The nervous system is often viewed as an isolated system that integrates information from the environment and host. Recently, there has been a renewed focus exploring the concept that the nervous system also communicates across biological systems. Specifically, several high profile studies have recently highlighted the importance of neuro-immune communication in the context of homeostasis, central nervous system disorders, host defense and injury. Here, we discuss the history of shared mechanisms and interconnectedness of the nervous, immune and epithelial compartments. In light of these overlapping mechanisms, it is perhaps unsurprising that neuro-immune-epithelial signaling plays a key role in regulating diverse biological phenomena. In this review, we explore recent breakthroughs in understanding neuro-immune signaling to highlight the importance of interdisciplinary approaches to biomedical research and the future development of novel therapeutics.

CD8(+) memory T cells provide anamnestic host defense against intracellular pathogens and cancer immunosurveillance but are also pathogenic in some autoimmune diseases. In mouse skin, there are two unique subsets of CD8(+) memory T cells, resident memory cells that reside long-term in steady state skin and recirculating memory cells that are transient. They have distinct mechanisms of recruitment, development, and maintenance in response to skin-derived signals. In this review, we will focus on these mechanisms and the functional relationship of these two types of CD8(+) memory cells with host defense and disease.

Transforming growth factor beta 1 (TGFβ) is known to be a regulator of autoimmunity. Loss of TGFβ leads to severe multi-organ autoimmunity in mice. In skin, role of TGFβ in suppressing autoimmunity is unclear.Determine whether Keratinocyte (KC)-derived TGFβ is required for skin immune homeostasis.We generated K14-CreERKC was the major source of TGFβ in epidermis. Topical tamoxifen application led to efficient TGFβ1 deletion. The expected acanthosis was observed but no inflammatory infiltrate or altered numbers of resident immune cells were evident. Similarly, Itgb6KC-derived TGFβ and epidermal TGFβ activation are not required to suppress skin autoimmunity in steady state.

The immune functions of epithelia-resident dendritic cells are influenced by epithelial-derived cytokines. Here we identified a communication form between tissue-resident dendritic cells and niche cells that allows direct intracellular material exchange between the parties. We show that many keratinocyte (KC)-specific molecules such as keratins and adhesion molecules could be detected in the epidermal-resident Langerhans cells (LCs) as mRNA and protein. Furthermore, KC-derived Cre led to genetic recombination in the LCs. We also found that LCs containing KC-derived material were more prone to migration. The KC-specific signatures were transferred from KCs to LCs through an exosome-independent mechanism that likely involved nanotubes/dendrites. The transfer of material between epithelial cells and epithelia-associated dendritic cells was not limited to mice or to KC-to-LC transfer. Taken together, these data suggest that the epithelial environment might have a long-term effect on dendritic cell biology and that genetic tools that specifically target epithelial cells also affect tissue-resident immune cells.

Poison ivy, poison oak, and poison sumac are the most common causes of clinically diagnosed allergic contact dermatitis in North America. Approximately 50% to 75% of the US adult population is clinically sensitive to poison ivy, oak, and sumac. We reviewed the botany and history of these plants; urushiol chemistry and pathophysiology, clinical features, and the prevalence of allergic contact dermatitis caused by these plants; and current postexposure treatment and preventive methods, including ongoing investigations in the development of a vaccine (immunotherapy). Although extensive efforts have been made to develop therapies that prevent and treat contact dermatitis to these plants, there lacks an entirely effective method, besides complete avoidance. There is a need for a better therapy to definitively prevent allergic contact dermatitis to these plants.

Background Transforming growth factor beta 1 (TGFβ) is known to be a regulator of autoimmunity. Loss of TGFβ leads to severe multi-organ autoimmunity in mice. In skin, role of TGFβ in suppressing autoimmunity is unclear. Objective Determine whether Keratinocyte (KC)-derived TGFβ is required for skin immune homeostasis. Methods We generated K14-CreER T2 TGFβ1 fl/fl ( TGFβ ΔKC ) mice allowing for tamoxifen-induced deletion of TGFβ1 in KC. The phenotype of skin was analyzed and compared to mice in which epidermal activation of TGFβ is impaired. Results KC was the major source of TGFβ in epidermis. Topical tamoxifen application led to efficient TGFβ1 deletion. The expected acanthosis was observed but no inflammatory infiltrate or altered numbers of resident immune cells were evident. Similarly, Itgb6 −/− x K14Cre Itgb8 f/f ( Itgb6 −/− Itgb8 ΔKC ) mice lacking both epidermal TGFβ-activating integrins showed no evidence of cutaneous inflammation. Conclusions KC-derived TGFβ and epidermal TGFβ activation are not required to suppress skin autoimmunity in steady state.

The bacterium Staphylococcus aureus is an important cause of skin infections and is also associated with the occurrence and severity of eczema. Langerhans cells (LCs), a specific subset of skin immune cells, participate in the immune response to S. aureus, but it is yet unclear how LCs recognize S. aureus. Therefore, we investigated the molecular mechanism underlying the interaction between LCs and S. aureus. We identified that wall teichoic acid, an abundant polymer on the S. aureus surface, is recognized by langerin, a receptor unique to LCs. This interaction allows LCs to discriminate S. aureus from other related staphylococcal species and initiates a proinflammatory response similar to that observed in patients with eczema. Our data therefore provide important new insights into the relationship between S. aureus, LCs, and eczema., Staphylococcus aureus is a major cause of skin and soft tissue infections and aggravator of the inflammatory skin disease atopic dermatitis (AD [eczema]). Epicutaneous exposure to S. aureus induces Th17 responses through skin Langerhans cells (LCs), which paradoxically contribute to host defense but also to AD pathogenesis. The molecular mechanisms underlying the interaction between S. aureus and LCs are poorly understood. Here we demonstrate that human LCs directly interact with S. aureus through the pattern recognition receptor langerin (CD207). Human, but not mouse, langerin interacts with S. aureus through the conserved β-N-acetylglucosamine (GlcNAc) modifications on wall teichoic acid (WTA), thereby discriminating S. aureus from other staphylococcal species. Importantly, the specific S. aureus WTA glycoprofile strongly influences the level of proinflammatory cytokines that are produced by in vitro-generated LCs. Finally, in a murine epicutaneous infection model, S. aureus strongly upregulated transcripts of Cxcl1, Il6, and Il17, which required the presence of both human langerin and WTA β-GlcNAc. Our findings provide molecular insight into the unique proinflammatory capacities of S. aureus in relation to skin inflammation.

Regulated activation of the cytokine TGFβ by integrins α(v)β(6) and α(v)β(8) expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV) infection, antigen-specific circulating memory CD8(+) T cells migrated into skin. In mice lacking α(v)β(6) and α(v)β(8) integrins (Itgb6(−/−)Itgb8(fl/fl)-K14-cre), the absence of epidermal activated TGFβ resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, that was rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory T cell pool.

In the skin, complex cellular networks maintain barrier function and immune homeostasis. Tightly regulated multicellular cascades are required to initiate innate and adaptive immune responses. Innate immune cells, particularly DCs and mast cells, are central to these networks. Early studies evaluated the function of these cells in isolation, but recent studies clearly demonstrate that cutaneous DCs (dermal DCs and Langerhans cells) physically interact with neighboring cells and are receptive to activation signals from surrounding cells, such as mast cells. These interactions amplify immune activation. In this review, we discuss the known functions of cutaneous DC populations and mast cells and recent studies highlighting their roles within cellular networks that determine cutaneous immune responses.

Tissue resident memory Th17 cells (TRM17) are the key cell type driving the chronic skin inflammation of psoriasis. Although IL-23 is strongly associated with autoimmunity and chronic inflammatory disorders including psoriasis, and anti-IL-23 biologic agents have remarkable efficacy in the treatment of psoriasis, the precise role of IL-23 in supporting IL-17-mediated skin inflammation remains unclear. In mice, we found that circulating memory T cells were dispensable for anamnestic protection from C. albicans skin infection, and TRM17 mediated protection from C. albicans reinfection required IL-23. Administration of anti-IL-23R antibody to dual Il17aCre Rosa26CAG-fl/fl-tdTomato Il17fThy1.1/Thy1.1 (17Fate) fate reporter mice following resolution of primary C. albicans infection resulted in a selective reduction in the number of CD69+CD103+TRM17 cells in skin compared with isotype controls. TRM17 proliferation was reduced and survival was unaffected. CD301b+ dermal dendritic cells (dDC) were an obligate source of IL-23 that supported TRM17 maintenance in skin after C. albicans challenge. These data demonstrate that locally produced IL-23 promotes in situ TRM17 proliferation to support their long term retention in skin. In normal human skin, we identified dermal cDC2 as the principal source of IL-23, although keratinocytes and CD4+ T cells were additional sources of IL-23 in psoriasis skin. Analysis of human psoriasis skin before and after clinical anti-IL-23 therapy revealed reduced TRM17 number and proliferation index, suggesting that targeted depletion of pathogenic TRM17 is the major mechanism by which anti-IL-23 therapy induces uniquely durable disease-free intervals in psoriasis patients.

Summary Following antigen-driven expansion in lymph node, transforming growth factor-β (TGFβ) is required for differentiation of skin-recruited CD8+ T cell effectors into epidermal resident memory T (Trm) cells and their epidermal persistence. We found that the source of TGFβ -supporting Trm cells was autocrine. In addition, antigen-specific Trm cells that encountered cognate antigen in the skin, and bystander Trm cells that did not, both displayed long-term persistence in the epidermis under steady-state conditions. However, when the active-TGFβ was limited or when new T cell clones were recruited into the epidermis, antigen-specific Trm cells were more efficiently retained than bystander Trm cells. Genetically enforced TGFβR signaling allowed bystander Trm cells to persist in the epidermis as efficiently as antigen-specific Trm cells in both contexts. Thus, competition between T cells for active TGFβ represents an unappreciated selective pressure that promotes the accumulation and persistence of antigen-specific Trm cells in the epidermal niche.

The Neurokinin 1 Receptor (NK1R), which binds Substance P, is expressed in discrete populations of neurons throughout the nervous system, where it has numerous roles including the modulation of pain and affective behaviors. Here, we report the generation of a NK1R-CreER knockin allele, in which CreERT2 replaces the coding sequence of the TACR1 gene (encoding NK1R) in order to gain genetic access to these cells. We find that the NK1R-CreER allele mediates recombination in many regions of the nervous system that are important in pain and anxiety including the amygdala, hypothalamus, frontal cortex, raphe nucleus, and dorsal horn of the spinal cord. Other cell types that are labeled by this allele include amacrine cells in the retina and fibroblasts in the skin. Thus, the NK1R-CreER mouse line is a valuable new tool for conditional gene manipulation enabling the visualization and manipulation of cells that express NK1R.

International audience; Cells of the immune system that reside in barrier epithelia provide a first line of defense against pathogens. Langerhans cells (LCs) and CD8+ tissue-resident memory T cells (TRM cells) require active transforming growth factor-beta1 (TGF-beta) for epidermal residence. Here we found that integrins alphavbeta6 and alphavbeta8 were expressed in non-overlapping patterns by keratinocytes (KCs) and maintained the epidermal residence of LCs and TRM cells by activating latent TGF-beta. Similarly, the residence of dendritic cells and TRM cells in the small intestine epithelium also required alphavbeta6. Treatment of the skin with ultraviolet irradiation decreased integrin expression on KCs and reduced the availability of active TGF-beta, which resulted in LC migration. Our data demonstrated that regulated activation of TGF-beta by stromal cells was able to directly control epithelial residence of cells of the immune system through a novel mechanism of intercellular communication

Keratinocytes (KCs) that form the epidermis create a unique barrier niche for cells of the immune system such as Langerhans cells (LCs) and CD8+ resident memory T cells (TRM). These leukocytes provide host-defense but also initiate and maintain autoimmune skin diseases. Hence, elucidating the mechanisms by which CD8+ TRM and LC maintain epidermal residency is of great therapeutic interest. Both cell types require active TGFβ1 to maintain their steady-state epidermal retention. In the epidermis, inactive LAP-TGFβ1 is exclusively activated into active TGFβ1 by integrins ανβ6 and ανβ8 expressed by KCs. However, the relationship between TGFβ1 and LC migration in response to inflammatory stimuli remains unknown. To determine whether enforced TGFβ1 signaling can overcome inflammation-induce LC migration, we generated huLangerin-CreERT2x TGFβRI-CALxL mice (TGFβR1-CALC) that allow for tamoxifen-induced ligand-independent TGFβRI signaling. Enforced TGFβRI signaling in LC prevented migration in response to UVB, chemical haptens, C. albicans epicutaneous infection as well as dermal injection of TNFα and IL1β. LC from TGFβR1-CALC mice did not egress from the epidermis or enter the draining lymph nodes. Notably, in WT mice, we did not observe reduced KC expression of integrin ανβ6 or ανβ8 and levels of pSMAD2 in LC did not decrease in inflammatory contexts. Thus, although enforced TGFβRI signaling can overcome inflammation-induced migratory signals, but the loss of TGFβRI signaling is not required for LC migration. These data are consistent with a model in which TGFβRI signaling drives a LC-intrinsic retention program under homeostatic conditions that is overcome or inhibited by inflammatory cues.

IL-17A is the original member of the IL-17 family of cytokines. Among the IL-17 family, IL-17F shares the most homology with IL-17A at the amino acid level. IL-17A and IL-17F exist as homodimers and also form a heterodimer (IL-17AF). All of these cytokine dimers signal through the same IL-17RA:IL-17RC receptor complex, but the ligands exhibit different signaling strengths (IL-17A > IL-17AF > IL-17F). We previously showed that IL-17 signaling is critical for immunity against oropharyngeal candidiasis (OPC), an opportunistic infection of the oral mucosa caused by the commensal fungus C. albicans. Mice lacking IL-17RA, IL-17RC, or the adaptor ACT1 all have higher oral fungal burdens than wild type (WT) following oral infection with C. albicans. IL-17A deficient mice are also mildly susceptible to C. albicans oral infection, but blockade of IL-17F does not cause disease susceptibility. Furthermore, double blockade of IL-17A and IL-17F during OPC reveals a cooperative antifungal activity of IL-17A and IL-17F. However, the role of the IL-17AF heterodimer still remains poorly understood. Here, we took advantage of a dominant-negative mutation (IL-17F.S65L) that was previously identified in chronic mucocutaneous candidiasis disease (CMCD) patients. This mutation blocks the signals of IL-17F and IL-17AF but not IL-17A. Using CRISPR/Cas9 technology, we created mice with the analogous IL-17F S65L mutation. These IL-17FS65L/S65L mice showed a similar degree of susceptibility as IL-17A−/− mice though less than IL-17RA−/− mice upon C. albicans oral infection. This result suggests that IL-17AF contributes to protection against OPC.

Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus Candida albicans. IL-17 and IL-22 both mediate antifungal immunity yet activate distinct downstream signaling pathways. While much is known about IL-17-dependent immunity in OPC, the activities of IL-22 are less well delineated. We show that induction of Il22 is independent of Dectin-1, CARD9 and aryl hydrocarbon receptor (AhR) and is driven by IL-23 and the C. albicans pore forming peptide candidalysin. Despite similar induction requirements and cellular sources, IL-22 and IL-17 function non-redundantly during OPC and exert opposing roles in neutrophil recruitment. The IL-22 and IL-17 receptors are required in anatomically distinct locations; loss of IL-22RA1 in the oral basal epithelial layer (BEL) but not the suprabasal epithelial layer (SEL) causes susceptibility to OPC, whereas IL-17RA is needed in the SEL. Our data reveal that IL-22 is a major activator of STAT3 in the BEL during OPC. Moreover, loss of STAT3 in the BEL but not the SEL renders mice susceptible to OPC. Transcriptional profiling of RNASeq data linked IL-22/STAT3 to oral epithelial cell proliferation and survival, but also, unexpectedly, to driving an IL-17 gene signature. We show that IL-22 acts on the BEL to replenish the IL-17RA-expressing SEL, thereby restoring the ability of the oral epithelium to respond to IL-17. Consequently, IL-22 signaling in BEL ‘licenses’ IL-17R signaling in the oral epithelium, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis. This work also suggests that oral thrush in Jobs’ syndrome patients may be caused by STAT3 impairments in the oral epithelium, not just Th17 cells.

Psoriasis is a chronic, inflammatory, multisystem disease that affects up to 3.2% of the US population. This guideline addresses important clinical questions that arise in psoriasis management and care, providing recommendations on the basis of available evidence.