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Recent studies have demonstrated that ß-catenin in dendritic cells (DCs) serves as a key mediator in promoting both CD4 and CD8 T cell tolerance, although the mechanisms underlying how ß-catenin exerts its functions remain incompletely understood. Here, we report that activation of ß-catenin leads to the up-regulation of inhibitory molecule T-cell immunoglobulin and mucin domain 3 (Tim-3) in type 1 conventional DCs (cDC1s). Using a cDC1-targeted vaccine model with anti-DEC-205 engineered to express the melanoma antigen human gp100 (anti-DEC-205-hgp100), we demonstrated that CD11c-ß-cateninactive mice exhibited impaired cross-priming and memory responses of gp100-specific CD8 T (Pmel-1) cells upon immunization with anti-DEC-205-hgp100. Single-cell RNA sequencing (scRNA-seq) analysis revealed that ß-catenin in DCs negatively regulated transcription programs for effector function and proliferation of primed Pmel-1 cells, correlating with suppressed CD8 T cell immunity in CD11c-ß-cateninactive mice. Further experiments showed that treating CD11c-ß-cateninactive mice with an anti-Tim-3 antibody upon anti-DEC-205-hgp100 vaccination led to restored cross-priming and memory responses of gp100-specific CD8 T cells, suggesting that anti-Tim-3 treatment likely synergizes with DC vaccines to improve their efficacy. Indeed, treating B16F10-bearing mice with DC vaccines using anti-DEC-205-hgp100 in combination with anti-Tim-3 treatment resulted in significantly reduced tumor growth compared with treatment with the DC vaccine alone. Taken together, we identified the ß-catenin/Tim-3 axis as a potentially novel mechanism to inhibit anti-tumor CD8 T cell immunity and that combination immunotherapy of a DC-targeted vaccine with anti-Tim-3 treatment leads to improved anti-tumor efficacy.
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Colorectal cancer (CRC) is a complex and heterogeneous disease characterized by dysregulated interactions between tumor cells and the immune system. The tumor microenvironment plays a pivotal role in cancer initiation as well as progression, with myeloid immune cells such as dendritic cell and macrophage subsets playing diverse roles in cancer immunity. On one hand, they exert anti-tumor effects, but they can also contribute to tumor growth. The AOM/DSS colitis-associated cancer mouse model has emerged as a valuable tool to investigate inflammation-driven CRC. To understand the role of different leukocyte populations in tumor development, the preparation of single cell suspensions from tumors has become standard procedure for many types of cancer in recent years. However, in the case of AOM/DSS-induced colorectal tumors, this is still challenging and rarely described. For one, to be able to properly distinguish tumor-associated immune cells, separate processing of cancerous and surrounding colon tissue is essential. In addition, cell yield, due to the low tumor mass, viability, as well as preservation of cell surface epitopes are important for successful flow cytometric profiling of tumor-infiltrating leukocytes. Here we present a fast, simple, and economical step-by-step protocol for isolating colorectal tumor-associated leukocytes from AOM/DSS-treated mice. Furthermore, we demonstrate the feasibility of this protocol for high-dimensional flow cytometric identification of the different tumor-infiltrating leukocyte populations, with a specific focus on myeloid cell subsets.
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Neoplasias Colorrectales , Animales , Ratones , Azoximetano/efectos adversos , Modelos Animales de Enfermedad , Citometría de Flujo , Leucocitos/metabolismo , Microambiente TumoralRESUMEN
Tissue-resident memory CD8+ T cells (TRM) reside at sites of previous infection, providing protection against reinfection with the same pathogen. In the skin, TRM patrol the epidermis, where keratinocytes are the entry site for many viral infections. Epidermal TRM react rapidly to cognate antigen encounter with the secretion of cytokines and differentiation into cytotoxic effector cells, constituting a first line of defense against skin reinfection. Despite the important protective role of skin TRM, it has remained unclear, whether their reactivation requires a professional antigen-presenting cell (APC). We show here, using a model system that allows antigen targeting selectively to keratinocytes in a defined area of the skin, that limited antigen expression by keratinocytes results in rapid, antigen-specific reactivation of skin TRM. Our data identify epidermal Langerhans cells that cross-present keratinocyte-derived antigens, as the professional APC indispensable for the early reactivation of TRM in the epidermal layer of the skin.
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Linfocitos T CD8-positivos , Células de Langerhans , Humanos , Células T de Memoria , Reinfección/metabolismo , Epidermis , Antígenos , Memoria InmunológicaRESUMEN
The main cause of malignancy-related mortality is metastasis. Although metastatic progression is driven by diverse tumor-intrinsic mechanisms, there is a growing appreciation for the contribution of tumor-extrinsic elements of the tumor microenvironment, especially macrophages, which correlate with poor clinical outcomes. Macrophages consist of bone marrow-derived and tissue-resident populations. In contrast to bone marrow-derived macrophages, the transcriptional pathways that govern the pro-metastatic activities of tissue-resident macrophages (TRMs) remain less clear. Alveolar macrophages (AMs) are a TRM population with critical roles in tissue homeostasis and metastasis. Wnt/ß-catenin signaling is a hallmark of cancer and has been identified as a pathologic regulator of AMs in infection. We tested the hypothesis that ß-catenin expression in AMs enhances metastasis in solid tumor models. Using a genetic ß-catenin gain-of-function approach, we demonstrated that (a) enhanced ß-catenin in AMs heightened lung metastasis; (b) ß-catenin activity in AMs drove a dysregulated inflammatory program strongly associated with Tnf expression; and (c) localized TNF-α blockade abrogated this metastatic outcome. Last, ß-catenin gene CTNNB1 and TNF expression levels were positively correlated in AMs of patients with lung cancer. Overall, our findings revealed a Wnt/ß-catenin/TNF-α pro-metastatic axis in AMs with potential therapeutic implications against tumors refractory to the antineoplastic actions of TNF-α.
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Neoplasias Pulmonares , Macrófagos Alveolares , Humanos , Macrófagos Alveolares/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias Pulmonares/patología , Vía de Señalización Wnt , Microambiente TumoralRESUMEN
Psoriasis is an IL-23/IL-17-mediated inflammatory autoimmune dermatosis, and UVB may contribute to immunosuppression and ameliorate associated symptoms. One of the pathophysiology underlying UVB therapy is the production of cis-urocanic acid (cis-UCA) by keratinocytes. However, the detailed mechanism is yet to be fully understood. In this study, we found FLG expression and serum cis-UCA levels were significantly lower in patients with psoriasis than in healthy controls. We also noted that cis-UCA application inhibited psoriasiform inflammation through the reduction of Vγ4+ γδT17 cells in murine skin and draining lymph nodes. Meanwhile, CCR6 was downregulated on γδT17 cells, which would suppress the inflammatory reaction at a distal skin site. We revealed that the 5-hydroxytryptamine receptor 2A, the known cis-UCA receptor, was highly expressed on Langerhans cells in the skin. cis-UCA also inhibited IL-23 expression and induced PD-L1 on Langerhans cells, leading to the attenuated proliferation and migration of γδT-cells. Compared to the isotype control, α-PD-L1 treatment in vivo could reverse the antipsoriatic effects of cis-UCA. PD-L1 expression on Langerhans cells was sustained through the cis-UCA-induced mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. These findings uncover the cis-UCA-induced PD-L1-mediated immunosuppression on Langerhans cells, which facilitates the resolution of inflammatory dermatoses.
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Dermatitis , Psoriasis , Ácido Urocánico , Humanos , Ratones , Animales , Células de Langerhans , Imiquimod/farmacología , Antígeno B7-H1 , Inflamación , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Interleucina-23/farmacología , Rayos UltravioletaRESUMEN
The skin and the oral mucosa represent interfaces to the environment that are constantly exposed to pathogens and harmless foreign antigens such as commensal bacteria. Both barrier organs share the presence of Langerhans cells (LC), distinctive members of the heterogeneous family of antigen-presenting dendritic cells (DC) that have the unique ability to promote tolerogenic as well as inflammatory immune responses. While skin LC have been extensively studied in the past decades, less is known about the function of oral mucosal LC. Despite similar transcriptomic signatures, skin and oral mucosal LC differ greatly in their ontogeny and development. In this review article, we will summarize the current knowledge on LC subsets in the skin compared to the oral mucosa. We will discuss the similarities and differences in their development, homeostasis, and function in the two barrier tissues, including their interaction with the local microbiota. In addition, this review will update recent advances on the role of LC in inflammatory skin and oral mucosal diseases.
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Células de Langerhans , Mucosa Bucal , Piel , Inmunidad , Antígenos , Células DendríticasRESUMEN
To specifically tailor immune responses to a given pathogenic threat, dendritic cells (DC) are highly heterogeneous and comprise many specialized subtypes, including conventional DC (cDC) and monocyte-derived DC (MoDC), each with distinct developmental and functional characteristics. However, the functional relationship between cDC and MoDC is not fully understood, as the overlapping phenotypes of certain type 2 cDC (cDC2) subsets and MoDC do not allow satisfactory distinction of these cells in the tissue, particularly during inflammation. However, precise cDC2 and MoDC classification is required for studies addressing how these diverse cell types control immune responses and is therefore currently one of the major interests in the field of cDC research. This review will revise murine cDC2 and MoDC biology in the steady state and under inflammatory conditions and discusses the commonalities and differences between ESAMlo cDC2, inflammatory cDC2, and MoDC and their relative contribution to the initiation, propagation, and regulation of immune responses.
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Células Dendríticas , Monocitos , Animales , Ratones , FenotipoRESUMEN
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various nonlymphoid tissues. DC are sentinels of the immune system present in almost every mammalian organ. Since they represent a rare cell population, DC need to be extracted from organs with protocols that are specifically developed for each tissue. This article provides detailed protocols for the preparation of single-cell suspensions from various mouse nonlymphoid tissues, including skin, intestine, lung, kidney, mammary glands, oral mucosa and transplantable tumors. Furthermore, our guidelines include comprehensive protocols for multiplex flow cytometry analysis of DC subsets and feature top tricks for their proper discrimination from other myeloid cells. With this collection, we provide guidelines for in-depth analysis of DC subsets that will advance our understanding of their respective roles in healthy and diseased tissues. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all coauthors, making it an essential resource for basic and clinical DC immunologists.
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Células Dendríticas , Piel , Animales , Humanos , Citometría de Flujo , Células Mieloides , Riñón , MamíferosRESUMEN
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human DC from lymphoid organs, and various non-lymphoid tissues. Within this chapter, detailed protocols are presented that allow for the generation of single-cell suspensions from mouse lymphohematopoietic tissues including spleen, peripheral lymph nodes, and thymus, with a focus on the subsequent analysis of DC by flow cytometry. However, prepared single-cell suspensions can be subjected to other applications including sorting and cellular enrichment procedures, RNA sequencing, Western blotting, and many more. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
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This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Recent studies have provided evidence for an increasing number of phenotypically distinct conventional DC (cDC) subsets that on one hand exhibit a certain functional plasticity, but on the other hand are characterized by their tissue- and context-dependent functional specialization. Here, we describe a selection of assays for the functional characterization of mouse and human cDC. The first two protocols illustrate analysis of cDC endocytosis and metabolism, followed by guidelines for transcriptomic and proteomic characterization of cDC populations. Then, a larger group of assays describes the characterization of cDC migration in vitro, ex vivo, and in vivo. The final guidelines measure cDC inflammasome and antigen (cross)-presentation activity. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
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Heterodimeric ß2 integrin surface receptors (CD11a-d/CD18) are specifically expressed by leukocytes that contribute to pathogen uptake, cell migration, immunological synapse formation and cell signaling. In humans, the loss of CD18 expression results in leukocyte adhesion deficiency syndrome (LAD-)1, largely characterized by recurrent severe infections. All available mouse models display the constitutive and ubiquitous knockout of either α or the common ß2 (CD18) subunit, which hampers the analysis of the cell type-specific role of ß2 integrins in vivo. To overcome this limitation, we generated a CD18 gene floxed mouse strain. Offspring generated from crossing with CD11c-Cre mice displayed the efficient knockdown of ß2 integrins, specifically in dendritic cells (DCs). Stimulated ß2-integrin-deficient splenic DCs showed enhanced cytokine production and the concomitantly elevated activity of signal transducers and activators of transcription (STAT) 1, 3 and 5, as well as the impaired expression of suppressor of cytokine signaling (SOCS) 2-6 as assessed in bone marrow-derived (BM) DCs. Paradoxically, these BMDCs also showed the attenuated expression of genes involved in inflammatory signaling. In line, in experimental autoimmune encephalomyelitis mice with a conditional DC-specific ß2 integrin knockdown presented with a delayed onset and milder course of disease, associated with lower frequencies of T helper cell populations (Th)1/Th17 in the inflamed spinal cord. Altogether, our mouse model may prove to be a valuable tool to study the leukocyte-specific functions of ß2 integrins in vivo.
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Antígenos CD18 , Células Dendríticas , Encefalomielitis Autoinmune Experimental , Inflamación , Animales , Antígenos CD18/genética , Antígenos CD18/metabolismo , Citocinas/metabolismo , Células Dendríticas/metabolismo , Encefalomielitis , Encefalomielitis Autoinmune Experimental/genética , Expresión Génica , Inflamación/genética , Síndrome de Deficiencia de Adhesión del Leucocito , RatonesRESUMEN
Non-destructive evaluation of plastically deformed metals, particularly diffraction line profile analysis (DLPA), is valuable both to estimate dislocation densities and arrangements and to validate microstructure-aware constitutive models. To date, the interpretation of whole line diffraction profiles relies on the use of semi-analytical models such as the extended convolutional multiple whole profile (eCMWP) method. This study introduces and validates two data-driven DLPA models to extract dislocation densities from experimentally gathered whole line diffraction profiles. Using two distinct virtual diffraction models accounting for both strain and instrument induced broadening, a database of virtual diffraction whole line profiles of Ta single crystals is generated using discrete dislocation dynamics. The databases are mined to create Gaussian process regression-based surrogate models, allowing dislocation densities to be extracted from experimental profiles. The method is validated against 11 experimentally gathered whole line diffraction profiles from plastically deformed Ta polycrystals. The newly proposed model predicts dislocation densities consistent with estimates from eCMWP. Advantageously, this data driven LPA model can distinguish broadening originating from the instrument and from the dislocation content even at low dislocation densities. Finally, the data-driven model is used to explore the effect of heterogeneous dislocation densities in microstructures containing grains, which may lead to more accurate data-driven predictions of dislocation density in plastically deformed polycrystals.
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Innate-like T cells, including invariant natural killer T cells, mucosal-associated invariant T cells, and γδ T cells, are present in various barrier tissues, including the lung, where they carry out protective responses during infections. Here, we investigate their roles during pulmonary pneumococcal infection. Following infection, innate-like T cells rapidly increase in lung tissue, in part through recruitment, but T cell antigen receptor activation and cytokine production occur mostly in interleukin-17-producing NKT17 and γδ T cells. NKT17 cells are preferentially located within lung tissue prior to infection, as are CD103+ dendritic cells, which are important both for antigen presentation to NKT17 cells and γδ T cell activation. Whereas interleukin-17-producing γδ T cells are numerous, granulocyte-macrophage colony-stimulating factor is exclusive to NKT17 cells and is required for optimal protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Animales , Línea Celular , Células Dendríticas/inmunología , Femenino , Humanos , Interferón gamma/inmunología , Interleucina-17/inmunología , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Infecciones Neumocócicas/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Streptococcus pneumoniae/inmunologíaRESUMEN
Sodium can accumulate in the skin at concentrations exceeding serum levels. A high sodium environment can lead to pathogenic T helper 17 cell expansion. Psoriasis is a chronic inflammatory skin disease in which IL-17âproducing T helper 17 cells play a crucial role. In an observational study, we measured skin sodium content in patients with psoriasis and in age-matched healthy controls by Sodium-23 magnetic resonance imaging. Patients with PASI > 5 showed significantly higher sodium and water content in the skin but not in other tissues than those with lower PASI or healthy controls. Skin sodium concentrations measured by Sodium-23 spectroscopy or by atomic absorption spectrometry in ashed-skin biopsies verified the findings with Sodium-23 magnetic resonance imaging. In vitro T helper 17 cell differentiation of naive CD4+ cells from patients with psoriasis markedly induced IL-17A expression under increased sodium chloride concentrations. The imiquimod-induced psoriasis mouse model replicated the human findings. Extracellular tracer Chromium-51-EDTA measurements in imiquimod- and sham-treated skin showed similar extracellular volumes, rendering excessive water of intracellular origin. Chronic genetic IL-17Aâdriven psoriasis mouse models underlined the role of IL-17A in dermal sodium accumulation and inflammation. Our data describe skin sodium as a pathophysiological feature of psoriasis, which could open new avenues for its treatment.
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Interleucina-17/metabolismo , Psoriasis/metabolismo , Piel/metabolismo , Sodio/análisis , Células Th17/inmunología , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Índice de Severidad de la Enfermedad , Piel/patología , Cloruro de Sodio/metabolismo , Espectrofotometría Atómica , Análisis EspectralRESUMEN
The spleen contains phenotypically and functionally distinct conventional dendritic cell (cDC) subpopulations, termed cDC1 and cDC2, which each can be divided into several smaller and less well-characterized subsets. Despite advances in understanding the complexity of cDC ontogeny by transcriptional programming, the significance of posttranslational modifications in controlling tissue-specific cDC subset immunobiology remains elusive. Here, we identified the cell-surface-expressed A-disintegrin-and-metalloproteinase 10 (ADAM10) as an essential regulator of cDC1 and cDC2 homeostasis in the splenic marginal zone (MZ). Mice with a CD11c-specific deletion of ADAM10 (ADAM10ΔCD11c) exhibited a complete loss of splenic ESAMhi cDC2A because ADAM10 regulated the commitment, differentiation, and survival of these cells. The major pathways controlled by ADAM10 in ESAMhi cDC2A are Notch, signaling pathways involved in cell proliferation and survival (e.g., mTOR, PI3K/AKT, and EIF2 signaling), and EBI2-mediated localization within the MZ. In addition, we discovered that ADAM10 is a molecular switch regulating cDC2 subset heterogeneity in the spleen, as the disappearance of ESAMhi cDC2A in ADAM10ΔCD11c mice was compensated for by the emergence of a Clec12a+ cDC2B subset closely resembling cDC2 generally found in peripheral lymph nodes. Moreover, in ADAM10ΔCD11c mice, terminal differentiation of cDC1 was abrogated, resulting in severely reduced splenic Langerin+ cDC1 numbers. Next to the disturbed splenic cDC compartment, ADAM10 deficiency on CD11c+ cells led to an increase in marginal metallophilic macrophage (MMM) numbers. In conclusion, our data identify ADAM10 as a molecular hub on both cDC and MMM regulating their transcriptional programming, turnover, homeostasis, and ability to shape the anatomical niche of the MZ.
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Proteína ADAM10/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Células Dendríticas/metabolismo , Proteínas de la Membrana/metabolismo , Proteína ADAM10/fisiología , Secretasas de la Proteína Precursora del Amiloide/fisiología , Animales , Células Presentadoras de Antígenos/metabolismo , Antígeno CD11c/metabolismo , Diferenciación Celular , Proliferación Celular , Femenino , Homeostasis , Tejido Linfoide/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Células Mieloides/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Procesamiento Proteico-Postraduccional/genética , Procesamiento Proteico-Postraduccional/fisiología , Transducción de Señal , Bazo/citología , Bazo/metabolismoRESUMEN
The original concept stated that immature dendritic cells (DC) act tolerogenically whereas mature DC behave strictly immunogenically. Meanwhile, it is also accepted that phenotypically mature stages of all conventional DC subsets can promote tolerance as steady-state migratory DC by transporting self-antigens to lymph nodes to exert unique functions on regulatory T cells. We propose that in vivo 1) there is little evidence for a tolerogenic function of immature DC during steady state such as CD4 T cell anergy induction, 2) all tolerance as steady-state migratory DC undergo common as well as subset-specific molecular changes, and 3) these changes differ by quantitative and qualitative markers from immunogenic DC, which allows one to clearly distinguish tolerogenic from immunogenic migratory DC.
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Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad , Diferenciación Celular , Movimiento Celular , Humanos , Inmunidad Celular , Modelos InmunológicosAsunto(s)
Células de Langerhans/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos de Superficie/metabolismo , Modelos Animales de Enfermedad , Humanos , Células de Langerhans/metabolismo , Lectinas Tipo C/metabolismo , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/patología , Recuento de Linfocitos , Lectinas de Unión a Manosa/metabolismo , Ratones , Ratones Endogámicos BALB C , Piel/citología , Piel/inmunología , Piel/parasitología , Piel/patología , Organismos Libres de Patógenos EspecíficosRESUMEN
Acute graft-versus-host disease (aGVHD) induced by allogenic hematopoietic stem cell transplantation is an immunological disorder in which donor lymphocytes attack recipient organs. It has been proven that recipient nonhematopoietic tissue cells, such as keratinocytes, are sufficient as immunological targets for allogenic donor T cells, whereas Langerhans cells (LCs) are potent professional hematopoietic antigen-presenting cells existing in the target epidermis and eliminated during the early phase of mucocutaneous aGVHD. Moreover, LCs have been reported to negatively regulate various types of immune responses. Here, we present data showing that initial depletion of recipient LCs exacerbates mucocutaneous lesions in a murine model of allogenic bone marrow transplantation-induced aGVHD. Furthermore, another murine model of mucocutaneous aGVHD induced in mice with keratinocytes genetically expressing chicken ovalbumin by transfer of ovalbumin-specific CD8+ OT-I cells also showed that LC-depleted recipient mice develop aggravated mucocutaneous disease owing to decreased apoptosis of skin-infiltrating OT-I cells. Moreover, coexisting LCs directly induce apoptosis and inhibit the proliferation of OT-I cells in vitro partially via B7 family proteins. Collectively, our results indicate that LCs negatively regulate mucocutaneous aGVHD-like lesions in situ by inhibiting the number of infiltrating CD8+ T cells.
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Trasplante de Médula Ósea/efectos adversos , Linfocitos T CD8-positivos/inmunología , Enfermedad Injerto contra Huésped/inmunología , Células de Langerhans/fisiología , Enfermedades de la Piel/inmunología , Enfermedad Aguda , Animales , Apoptosis , Antígenos B7/fisiología , Células Cultivadas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Inhibidor 1 de la Activación de Células T con Dominio V-Set/fisiologíaRESUMEN
In this issue of JEM, Lim et al. (https://doi.org/10.1084/jem.20191810) provide exciting new evidence that talin1 plays an essential role in dendritic cell (DC) maturation and activation. Using conditional knockout mice, they demonstrate that talin1 promotes the formation of a preassembled TLR-Myddosome signaling complex in steady-state DCs but not macrophages. This may explain why DCs respond faster and more vigorously to TLR ligand binding than their closely related macrophages.