RESUMEN
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.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Células Dendríticas/inmunología , Células de Langerhans/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Piel/inmunología , Linfocitos T/inmunología , Animales , Presentación de Antígeno , Movimiento Celular , Homeostasis , Humanos , Inflamación , Activación de Linfocitos , RatonesRESUMEN
Inflammatory pain results from the heightened sensitivity and reduced threshold of nociceptor sensory neurons due to exposure to inflammatory mediators. However, the cellular and transcriptional diversity of immune cell and sensory neuron types makes it challenging to decipher the immune mechanisms underlying pain. Here we used single-cell transcriptomics to determine the immune gene signatures associated with pain development in three skin inflammatory pain models in mice: zymosan injection, skin incision and ultraviolet burn. We found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development and identified cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels and metabolites to generate injury-specific neuroimmune interactomes, we also uncovered that thrombospondin-1 upregulated by immune cells upon injury inhibited nociceptor sensitization. This study lays the groundwork for identifying the neuroimmune axes that modulate pain in diverse disease contexts.
Asunto(s)
Nociceptores , Dolor , Animales , Ratones , Dolor/inmunología , Dolor/metabolismo , Nociceptores/metabolismo , Transcriptoma , Ratones Endogámicos C57BL , Inflamación/inmunología , Masculino , Macrófagos/inmunología , Macrófagos/metabolismo , Modelos Animales de Enfermedad , Trombospondina 1/metabolismo , Trombospondina 1/genética , Piel/inmunología , Piel/metabolismo , Piel/patología , Zimosan , Análisis de la Célula Individual , Neuroinmunomodulación , Perfilación de la Expresión Génica , Neutrófilos/inmunología , Neutrófilos/metabolismoRESUMEN
The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases.
Asunto(s)
Psoriasis/inmunología , Animales , Comorbilidad , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Ratones , Psoriasis/diagnóstico , Psoriasis/genética , Piel/inmunología , Piel/patología , Fenómenos Fisiológicos de la Piel/inmunologíaRESUMEN
The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratinocyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the microbiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for heightened ERV- expression in response to commensal colonization, leading to increased immune responses and tissue inflammation. Together, our results support the idea that the host may have co-opted its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-kingdom dialog that controls both tissue homeostasis and inflammation.
Asunto(s)
Retrovirus Endógenos/fisiología , Homeostasis , Inflamación/microbiología , Inflamación/patología , Microbiota , Animales , Bacterias/metabolismo , Cromosomas Bacterianos/genética , Dieta Alta en Grasa , Inflamación/inmunología , Inflamación/virología , Interferón Tipo I/metabolismo , Queratinocitos/metabolismo , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Nucleotidiltransferasas/metabolismo , Retroelementos/genética , Transducción de Señal , Piel/inmunología , Piel/microbiología , Linfocitos T/inmunología , Transcripción GenéticaRESUMEN
Cutaneous TRPV1+ neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1+ neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1+ neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1+ neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1+ neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation.
Asunto(s)
Inmunidad Innata/inmunología , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Células Receptoras Sensoriales/inmunología , Piel/inmunología , Canales Catiónicos TRPV/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Candida albicans/inmunología , Inflamación/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Optogenética/métodos , Piel/microbiología , Staphylococcus aureus/inmunología , Canales Catiónicos TRPV/genéticaRESUMEN
Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies.
Asunto(s)
Inmunidad Adaptativa , Quimiotaxis , Relojes Circadianos , Células Dendríticas/inmunología , Ganglios Linfáticos/inmunología , Vasos Linfáticos/inmunología , Piel/inmunología , Anciano , Animales , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Péptidos y Proteínas de Señalización del Ritmo Circadiano/metabolismo , Células Dendríticas/metabolismo , Femenino , Humanos , Ganglios Linfáticos/metabolismo , Vasos Linfáticos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Piel/metabolismo , Factores de TiempoRESUMEN
Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1ß. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.
Asunto(s)
Lepra Lepromatosa/inmunología , Lepra Tuberculoide/inmunología , Mycobacterium leprae/inmunología , Piel/inmunología , Adolescente , Adulto , Anciano , Femenino , Fibroblastos/inmunología , Fibroblastos/microbiología , Fibroblastos/patología , Perfilación de la Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Queratinocitos/inmunología , Queratinocitos/microbiología , Queratinocitos/patología , Lepra Lepromatosa/genética , Lepra Lepromatosa/microbiología , Lepra Lepromatosa/patología , Lepra Tuberculoide/genética , Lepra Tuberculoide/microbiología , Lepra Tuberculoide/patología , Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/patología , Masculino , Persona de Mediana Edad , Mycobacterium leprae/patogenicidad , RNA-Seq , Análisis de la Célula Individual , Piel/microbiología , Piel/patología , Linfocitos T/inmunología , Linfocitos T/microbiología , Linfocitos T/patología , TranscriptomaRESUMEN
The signals driving the adaptation of type 2 dendritic cells (DC2s) to diverse peripheral environments remain mostly undefined. We show that differentiation of CD11blo migratory DC2s-a DC2 population unique to the dermis-required IL-13 signaling dependent on the transcription factors STAT6 and KLF4, whereas DC2s in lung and small intestine were STAT6-independent. Similarly, human DC2s in skin expressed an IL-4 and IL-13 gene signature that was not found in blood, spleen and lung DCs. In mice, IL-13 was secreted homeostatically by dermal innate lymphoid cells and was independent of microbiota, TSLP or IL-33. In the absence of IL-13 signaling, dermal DC2s were stable in number but remained CD11bhi and showed defective activation in response to allergens, with diminished ability to support the development of IL-4+GATA3+ helper T cells (TH), whereas antifungal IL-17+RORγt+ TH cells were increased. Therefore, homeostatic IL-13 fosters a noninflammatory skin environment that supports allergic sensitization.
Asunto(s)
Comunicación Celular , Diferenciación Celular , Interleucina-13/metabolismo , Células de Langerhans/metabolismo , Piel/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Alérgenos/farmacología , Animales , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Células Cultivadas , Bases de Datos Genéticas , Humanos , Interleucina-13/genética , Células de Langerhans/efectos de los fármacos , Células de Langerhans/inmunología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismo , Transducción de Señal , Piel/citología , Piel/efectos de los fármacos , Piel/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología , TranscriptomaRESUMEN
Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6+, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.
Asunto(s)
Autoinmunidad , Encéfalo/inmunología , Linaje de la Célula , Encefalomielitis Autoinmune Experimental/inmunología , Intestinos/inmunología , Piel/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Traslado Adoptivo , Animales , Autoinmunidad/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Señalización del Calcio , Líquido Cefalorraquídeo/inmunología , Líquido Cefalorraquídeo/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Clorhidrato de Fingolimod/farmacología , Perfilación de la Expresión Génica , Genes Codificadores de los Receptores de Linfocitos T , Células HEK293 , Humanos , Inmunosupresores/farmacología , Intestinos/efectos de los fármacos , Microscopía Intravital , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Esclerosis Múltiple Recurrente-Remitente/genética , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Fenotipo , Estudios Prospectivos , RNA-Seq , Receptores CXCR6/genética , Receptores CXCR6/metabolismo , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Análisis de la Célula Individual , Piel/efectos de los fármacos , Piel/metabolismo , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/trasplante , TranscriptomaRESUMEN
Skin inflammation is potentiated by coordinated epithelial and immune cell metabolism. In this issue of Immunity, Subudhi and Konieczny et al. delineate how HIF1α regulates epithelial cell glycolysis during psoriasis. In turn, lactate is a byproduct that augments type 17 γδ T cell responses to sustain inflammatory skin disease.
Asunto(s)
Células Epiteliales , Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Psoriasis , Piel , Animales , Humanos , Enfermedad Crónica , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Psoriasis/inmunología , Psoriasis/metabolismo , Piel/inmunología , Piel/patología , Piel/metabolismoRESUMEN
Following tissue damage, epithelial stem cells (SCs) are mobilized to enter the wound, where they confront harsh inflammatory environments that can impede their ability to repair the injury. Here, we investigated the mechanisms that protect skin SCs within this inflammatory environment. Characterization of gene expression profiles of hair follicle SCs (HFSCs) that migrated into the wound site revealed activation of an immune-modulatory program, including expression of CD80, major histocompatibility complex class II (MHCII), and CXC motif chemokine ligand 5 (CXCL5). Deletion of CD80 in HFSCs impaired re-epithelialization, reduced accumulation of peripherally generated Treg (pTreg) cells, and increased infiltration of neutrophils in wounded skin. Importantly, similar wound healing defects were also observed in mice lacking pTreg cells. Our findings suggest that upon skin injury, HFSCs establish a temporary protective network by promoting local expansion of Treg cells, thereby enabling re-epithelialization while still kindling inflammation outside this niche until the barrier is restored.
Asunto(s)
Antígeno B7-1 , Folículo Piloso , Inflamación , Piel , Células Madre , Linfocitos T Reguladores , Cicatrización de Heridas , Animales , Linfocitos T Reguladores/inmunología , Ratones , Cicatrización de Heridas/inmunología , Piel/inmunología , Piel/lesiones , Piel/patología , Células Madre/inmunología , Células Madre/metabolismo , Inflamación/inmunología , Folículo Piloso/inmunología , Antígeno B7-1/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Repitelización/inmunología , Movimiento Celular/inmunología , Proliferación CelularRESUMEN
Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.
Asunto(s)
Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Interleucina-17 , Animales , Humanos , Interleucina-17/metabolismo , Interleucina-17/inmunología , Ratones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Piel/inmunología , Piel/patología , Piel/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 1/genética , Psoriasis/inmunología , Psoriasis/metabolismo , Epitelio/inmunología , Epitelio/metabolismo , Ratones Noqueados , Transducción de Señal/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Modelos Animales de Enfermedad , Ácido Láctico/metabolismo , Enfermedad Crónica , Inflamación/inmunología , Ratones Endogámicos C57BLRESUMEN
Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.
Asunto(s)
Inmunidad Adaptativa , Bacterias/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Microbiota/inmunología , Piel/inmunología , Linfocitos T/inmunología , Animales , Regulación de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Ratones , Ratones TransgénicosRESUMEN
Skin wounds heal by coordinated induction of inflammation and tissue repair, but the initiating events are poorly defined. Here we uncover a fundamental role of commensal skin microbiota in this process and show that it is mediated by the recruitment and the activation of type I interferon (IFN)-producing plasmacytoid DC (pDC). Commensal bacteria colonizing skin wounds trigger activation of neutrophils to express the chemokine CXCL10, which recruits pDC and acts as an antimicrobial protein to kill exposed microbiota, leading to the formation of CXCL10-bacterial DNA complexes. These complexes and not complexes with host-derived DNA activate pDC to produce type I IFNs, which accelerate wound closure by triggering skin inflammation and early T cell-independent wound repair responses, mediated by macrophages and fibroblasts that produce major growth factors required for healing. These findings identify a key function of commensal microbiota in driving a central innate wound healing response of the skin.
Asunto(s)
Células Dendríticas/inmunología , Fibroblastos/inmunología , Macrófagos/inmunología , Microbiota/inmunología , Neutrófilos/inmunología , Piel/inmunología , Animales , Células Cultivadas , Quimiocina CXCL10/metabolismo , Humanos , Inmunidad Innata , Inflamación , Interferón Tipo I/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piel/patología , Simbiosis , Cicatrización de HeridasRESUMEN
The intestine and skin are distinct microenvironments with unique physiological functions and are continually exposed to diverse environmental challenges. Host adaptation at these sites is an active process that involves interaction between immune cells and tissue cells. Regulatory T cells (Treg cells) play a pivotal role in enforcing homeostasis at barrier surfaces, illustrated by the development of intestinal and skin inflammation in diseases caused by primary deficiency in Treg cells. Treg cells at barrier sites are phenotypically distinct from their lymphoid-organ counterparts, and these 'tissue' signatures often reflect their tissue-adapted function. We discuss current understanding of Treg cell adaptation in the intestine and skin, including unique phenotypes, functions and metabolic demands, and how increased knowledge of Treg cells at barrier sites might guide precision medicine therapies.
Asunto(s)
Intestinos/inmunología , Piel/inmunología , Linfocitos T Reguladores/inmunología , Adaptación Fisiológica , Animales , Ambiente , Humanos , Ratones , Timo/inmunologíaRESUMEN
Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.
Asunto(s)
Alérgenos/inmunología , Dermatitis Atópica/inmunología , Mastocitos/inmunología , Nociceptores/inmunología , Pyroglyphidae/inmunología , Animales , Comunicación Celular/inmunología , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Mastocitos/metabolismo , Ratones Noqueados , Nociceptores/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Piel/citología , Piel/inmunología , Canales Catiónicos TRPV/metabolismo , Taquicininas/genética , Taquicininas/metabolismoRESUMEN
Here we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44- ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation that exhibits ILC3 features, including RORγt, enabling the conversion into IL-17-producing cells in response to IL-1ß and IL-23. We also report a role for transforming growth factor-ß in promoting the conversion of c-Kit- ILC2s into RORγt-expressing cells by inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells. This switch was dependent on RORγt and the downregulation of GATA-3. IL-4 was able to reverse this event, supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance because a subset of RORγt+ ILC2s express the skin-homing receptor CCR10, and the frequencies of IL-17-producing ILC3s are increased at the expense of ILC2s within the lesional skin of patients with psoriasis.
Asunto(s)
Interleucina-17/inmunología , Linfocitos/inmunología , Psoriasis/patología , Piel/patología , Células Cultivadas , Humanos , Interleucina-1beta/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Interleucina-4/inmunología , Linfocitos/citología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Psoriasis/inmunología , Receptores CCR10/metabolismo , Piel/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Emerging data show that tissue-resident memory T (TRM) cells play an important protective role at murine and human barrier sites. TRM cells in the epidermis of mouse skin patrol their surroundings and rapidly respond when antigens are encountered. However, whether a similar migratory behavior is performed by human TRM cells is unclear, as technology to longitudinally follow them in situ has been lacking. To address this issue, we developed an ex vivo culture system to label and track T cells in fresh skin samples. We validated this system by comparing in vivo and ex vivo properties of murine TRM cells. Using nanobody labeling, we subsequently demonstrated in human ex vivo skin that CD8+ TRM cells migrated through the papillary dermis and the epidermis, below sessile Langerhans cells. Collectively, this work allows the dynamic study of resident immune cells in human skin and provides evidence of tissue patrol by human CD8+ TRM cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Memoria Inmunológica , Piel/inmunología , Animales , Antígenos/inmunología , Línea Celular Tumoral , Movimiento Celular/inmunología , Epidermis/inmunología , Epidermis/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Ratones , Especificidad de Órganos/inmunología , Anticuerpos de Dominio Único/inmunología , Piel/metabolismo , Vacunas de ADN/genética , Vacunas de ADN/inmunologíaRESUMEN
The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.