Chronic ultraviolet (UV) radiation exposure is the greatest risk factor for cutaneous squamous cell carcinoma (cSCC) development, and compromised immunity accelerates this risk. Having previously ...identified that epidermal Langerhans cells (LC) facilitate the expansion of UV-induced mutant keratinocytes (KC), we sought to more fully elucidate the immune pathways critical to cutaneous carcinogenesis and to identify potential targets of intervention. Herein, we reveal that chronic UV induces and LC enhance a local immune shift toward RORγt+ interleukin (IL)-22/IL-17A-producing cells that occurs in the presence or absence of T cells while identifying a distinct RORγt+ Sca-1+ CD103+ ICOS+ CD2
CCR6+ intracellular CD3+ cutaneous innate lymphoid cell type-3 (ILC3) population (uvILC3) that is associated with UV-induced mutant KC growth. We further show that mutant KC clone size is markedly reduced in the absence of RORγt+ lymphocytes or IL-22, both observed in association with expanding KC clones, and find that topical application of a RORγ/γt inhibitor during chronic UV exposure reduces local expression of IL-22 and IL-17A while markedly limiting mutant p53 KC clonal expansion. We implicate upstream Toll-like receptor signaling in driving this immune response to chronic UV exposure, as MyD88/Trif double-deficient mice also show substantially reduced p53 island number and size. These data elucidate key immune components of chronic UV-induced cutaneous carcinogenesis that might represent targets for skin cancer prevention.
An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ–positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, ...comprising at least two 5-day courses of Ara-C (1 g/m2 per day) plus cladribine (9 mg/m2 per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.
•Patients with LCH, risk organs, refractory to standard VBL-steroid regimen have a poor survival, ∼30%.•In a phase 2 study, with 5 years' median follow-up, cladribine and Ara-C was shown to improve the survival up to 85% for this group.
Langerhans cell histiocytosis (LCH) is a rare clonal granulomatous disease that affects mainly children. LCH can involve various tissues such as bone, skin, lung, bone marrow, lymph nodes, and the ...central nervous system, and is frequently responsible for functional sequelae. The pathophysiology of LCH is unclear, but the uncontrolled proliferation of Langerhans cells (LCs) is believed to be the primary event in the formation of granulomas. The present study was designed to further investigate the nature of proliferating cells and the immune mechanisms involved in the LCH granulomas.
Biopsies (n = 24) and/or blood samples (n = 25) from 40 patients aged 0.25 to 13 y (mean 7.8 y), were studied to identify cells that proliferate in blood and granulomas. We found that the proliferating index of LCs was low ( approximately 1.9%), and we did not observe expansion of a monocyte or dendritic cell compartment in patients. We found that LCH lesions were a site of active inflammation, tissue remodeling, and neo-angiogenesis, and the majority of proliferating cells were endothelial cells, fibroblasts, and polyclonal T lymphocytes. Within granulomas, interleukin 10 was abundant, LCs expressed the TNF receptor family member RANK, and CD4(+) CD25(high) FoxP3(high) regulatory T cells (T-regs) represented 20% of T cells, and were found in close contact with LCs. FoxP3(+) T-regs were also expanded compared to controls, in the blood of LCH patients with active disease, among whom seven out of seven tested exhibited an impaired skin delayed-type hypersensitivity response. In contrast, the number of blood T-regs were normal after remission of LCH.
These findings indicate that LC accumulation in LCH results from survival rather than uncontrolled proliferation, and is associated with the expansion of T-regs. These data suggest that LCs may be involved in the expansion of T-regs in vivo, resulting in the failure of the host immune system to eliminate LCH cells. Thus T-regs could be a therapeutic target in LCH.
Skin-derived dendritic cells (DCs) play a crucial role in the maintenance of immune homeostasis due to their role in antigen trafficking from the skin to the draining lymph nodes (dLNs). To quantify ...the spatiotemporal regulation of skin-derived DCs in vivo, we generated knock-in mice expressing the photoconvertible fluorescent protein KikGR. By exposing the skin or dLN of these mice to violet light, we were able to label and track the migration and turnover of endogenous skin-derived DCs. Langerhans cells and CD103(+)DCs, including Langerin(+)CD103(+)dermal DCs (DDCs), remained in the dLN for 4-4.5 days after migration from the skin, while CD103(-)DDCs persisted for only two days. Application of a skin irritant (chemical stress) induced a transient >10-fold increase in CD103(-)DDC migration from the skin to the dLN. Tape stripping (mechanical injury) induced a long-lasting four-fold increase in CD103(-)DDC migration to the dLN and accelerated the trafficking of exogenous protein antigens by these cells. Both stresses increased the turnover of CD103(-)DDCs within the dLN, causing these cells to die within one day of arrival. Therefore, CD103(-)DDCs act as sentinels against skin invasion that respond with increased cellular migration and antigen trafficking from the skin to the dLNs.
HIV-1 acquisition occurs most commonly after sexual contact. To establish infection, HIV-1 must infect cells that support high-level replication, namely CD4+ T cells, which are absent from the ...outermost genital epithelium. Dendritic cells (DCs), present in mucosal epithelia, potentially facilitate HIV-1 acquisition. We show that vaginal epithelial DCs, termed CD1a+ VEDCs, are unlike other blood- and tissue-derived DCs because they express langerin but not DC-SIGN, and unlike skin-based langerin+ DC subset Langerhans cells (LCs), they do not harbor Birbeck granules. Individuals primarily acquire HIV-1 that utilizes the CCR5 receptor (termed either R5 or R5X4) during heterosexual transmission, and the mechanism for the block against variants that only use the CXCR4 receptor (classified as X4) remains unclear. We show that X4 as compared with R5 HIV-1 shows limited to no replication in CD1a+ VEDCs. This differential replication occurs after fusion, suggesting that receptor usage influences postentry steps in the virus life cycle. Furthermore, CD1a+ VEDCs isolated from HIV-1-infected virologically suppressed women harbor HIV-1 DNA. Thus, CD1a+ VEDCs are potentially infected early during heterosexual transmission and also retain virus during treatment. Understanding the interplay between HIV-1 and CD1a+ VEDCs is important for future prevention and cure strategies.
Colony stimulating factor-1 (Csf-1) receptor and its ligand Csf-1 control macrophage development, maintenance, and function. The development of both Langerhans cells (LCs) and microglia is highly ...dependent on Csf-1 receptor signaling but independent of Csf-1. Here we show that in both mice and humans, interleukin-34 (IL-34), an alternative ligand for Csf-1 receptor, is produced by keratinocytes in the epidermis and by neurons in the brain. Mice lacking IL-34 displayed a marked reduction of LCs and a decrease of microglia, whereas monocytes, dermal, and lymphoid tissue macrophages and DCs were unaffected. We identified IL-34 as a nonredundant cytokine for the development of LCs during embryogenesis as well as for their homeostasis in the adult skin. Whereas inflammation-induced repopulation of LCs appears to be dependent on Csf-1, once inflammation is resolved, LC survival is again IL-34-dependent. In contrast, microglia and their yolk sac precursors develop independently of IL-34 but rely on it for their maintenance in the adult brain.
► IL-34 is critical for the development and maintenance of LCs ► IL-34 is required for LC maintenance but not monocyte-derived repopulation in inflammation ► IL-34 is critical for the homeostasis of adult microglia ► IL-34 protein is produced in the epidermis and brain of mice and humans
The mechanisms that initiate T helper type 2 (T(H)2) responses are poorly understood. Here we demonstrate that cysteine protease-induced T(H)2 responses occur via 'cooperation' between migratory ...dermal dendritic cells (DCs) and basophils positive for interleukin 4 (IL-4). Subcutaneous immunization with papain plus antigen induced reactive oxygen species (ROS) in lymph node DCs and in dermal DCs and epithelial cells of the skin. ROS orchestrated T(H)2 responses by inducing oxidized lipids that triggered the induction of thymic stromal lymphopoietin (TSLP) by epithelial cells mediated by Toll-like receptor 4 (TLR4) and the adaptor protein TRIF; by suppressing production of the T(H)1-inducing molecules IL-12 and CD70 in lymph node DCs; and by inducing the DC-derived chemokine CCL7, which mediated recruitment of IL-4(+) basophils to the lymph node. Thus, the T(H)2 response to cysteine proteases requires DC-basophil cooperation via ROS-mediated signaling.
Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, ...mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.
Langerhans cells (LCs) play a pivotal role in skin homeostasis, and the heterogeneity of LCs has long been considered. In this study, we have identified two steady-state (LC1 and LC2) and two ...activated LC subsets in the epidermis of human skin and in LCs derived from CD34+ hemopoietic stem cells (HSC-LCs) by utilizing single-cell RNA sequencing and mass cytometry. Analysis of HSC-LCs at multiple time-points during differentiation revealed that EGR1 and Notch signaling were among the top pathways regulating the bifurcation of LC1 and LC2. LC1 were characterized as classical LCs, mainly related to innate immunity and antigen processing. LC2 were similar to monocytes or myeloid dendritic cells, involving in immune responses and leukocyte activation. LC1 remained stable under inflammatory microenvironment, whereas LC2 were prone to being activated and demonstrated elevated expression of immuno-suppressive molecules. We revealed distinct human LC subsets that require different developmental regulation and orchestrate reciprocal functions.
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•Two steady-state and two activated LC subsets are revealed in human skin•LC1 and LC2 are phenotypically and functionally distinct•SPI1, EGR1, and Notch signaling regulate LC1/LC2 fate specification and bifurcation•LC2 are increased in skin lesion of psoriasis, expressing immuno-regulatory markers
The heterogeneity of Langerhans cells has long been considered. Liu et al. reveal four subpopulations of primary and HSC-derived Langerhans cells in human, which are phenotypically and functionally distinct and require different developmental regulation.
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