RESUMEN
Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aß plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aß plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3ß-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aß involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.
Asunto(s)
Enfermedad de Alzheimer , Microglía , Animales , Ratones , Humanos , Microglía/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/patología , Placa Amiloide/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Quinasa Syk/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismoRESUMEN
Group 1 innate lymphoid cells (ILC1s) are cytotoxic and interferon gamma-producing lymphocytes lacking antigen-specific receptors, which include ILC1s and natural killer (NK) cells. In mice, ILC1s differ from NK cells, as they develop independently of the NK-specifying transcription factor EOMES, while requiring the repressor ZFP683 (ZNF683 in humans) for tissue residency. Here we identify highly variable ILC1 subtypes across tissues through investigation of human ILC1 diversity by single-cell RNA sequencing and flow cytometry. The intestinal epithelium contained abundant mature EOMES- ILC1s expressing PRDM1 rather than ZNF683, alongside a few immature TCF7+PRDM1- ILC1s. Other tissues harbored NK cells expressing ZNF683 and EOMES transcripts; however, EOMES protein content was variable. These ZNF683+ NK cells are tissue-imprinted NK cells phenotypically resembling ILC1s. The tissue ILC1-NK spectrum also encompassed conventional NK cells and NK cells distinguished by PTGDS expression. These findings establish a foundation for evaluating phenotypic and functional changes within the NK-ILC1 spectrum in diseases.
Asunto(s)
Inmunidad Innata , Células Asesinas Naturales , Linfocitos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas de Dominio T Box , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Linfocitos/inmunología , Linfocitos/metabolismo , Análisis de la Célula Individual , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Animales , Ratones , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/genéticaRESUMEN
Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we showed that Aiolos, an Ikaros zinc-finger family member encoded by Ikzf3, acted as a regulator of IEL activation. Ikzf3-/- CD8αα+ IELs had elevated expression of NK receptors, cytotoxic enzymes, cytokines and chemokines. Single-cell RNA sequencing of Ikzf3-/- and Ikzf3+/+ IELs showed an amplified effector machinery in Ikzf3-/- CD8αα+ IELs compared to Ikzf3+/+ counterparts. Ikzf3-/- CD8αα+ IELs had increased responsiveness to interleukin-15, which explained a substantial part, but not all, of the observed phenotypes. Aiolos binding sites were close to those for the transcription factors STAT5 and RUNX, which promote interleukin-15 signaling and cytolytic programs, and Ikzf3 deficiency partially increased chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency in mice enhanced susceptibility to colitis, underscoring the relevance of Aiolos in regulating the effector function in IELs.
Asunto(s)
Linfocitos Intraepiteliales , Factores de Transcripción , Animales , Ratones , Antígenos CD8/metabolismo , Interleucina-15/metabolismo , Mucosa Intestinal/metabolismo , Linfocitos Intraepiteliales/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Checkpoint immunotherapy unleashes T cell control of tumors, but is undermined by immunosuppressive myeloid cells. TREM2 is a myeloid receptor that transmits intracellular signals that sustain microglial responses during Alzheimer's disease. TREM2 is also expressed by tumor-infiltrating macrophages. Here, we found that Trem2-/- mice are more resistant to growth of various cancers than wild-type mice and are more responsive to anti-PD-1 immunotherapy. Furthermore, treatment with anti-TREM2 mAb curbed tumor growth and fostered regression when combined with anti-PD-1. scRNA-seq revealed that both TREM2 deletion and anti-TREM2 are associated with scant MRC1+ and CX3CR1+ macrophages in the tumor infiltrate, paralleled by expansion of myeloid subsets expressing immunostimulatory molecules that promote improved T cell responses. TREM2 was expressed in tumor macrophages in over 200 human cancer cases and inversely correlated with prolonged survival for two types of cancer. Thus, TREM2 might be targeted to modify tumor myeloid infiltrates and augment checkpoint immunotherapy.
Asunto(s)
Inmunoterapia , Glicoproteínas de Membrana/metabolismo , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/metabolismo , Animales , Anticuerpos Monoclonales/uso terapéutico , Receptor 1 de Quimiocinas CX3C/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/metabolismo , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Metilcolantreno/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/inducido químicamente , Neoplasias/patología , Pronóstico , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Microambiente TumoralRESUMEN
Chikungunya virus (CHIKV), an emerging alphavirus, has infected millions of people. However, the factors modulating disease outcome remain poorly understood. Here, we show in germ-free mice or in oral antibiotic-treated conventionally housed mice with depleted intestinal microbiomes that greater CHIKV infection and spread occurs within 1 day of virus inoculation. Alteration of the microbiome alters TLR7-MyD88 signaling in plasmacytoid dendritic cells (pDCs) and blunts systemic production of type I interferon (IFN). Consequently, circulating monocytes express fewer IFN-stimulated genes and become permissive for CHIKV infection. Reconstitution with a single bacterial species, Clostridium scindens, or its derived metabolite, the secondary bile acid deoxycholic acid, can restore pDC- and MyD88-dependent type I IFN responses to restrict systemic CHIKV infection and transmission back to vector mosquitoes. Thus, symbiotic intestinal bacteria modulate antiviral immunity and levels of circulating alphaviruses within hours of infection through a bile acid-pDC-IFN signaling axis, which affects viremia, dissemination, and potentially transmission.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Fiebre Chikungunya/patología , Microbioma Gastrointestinal , Interferón Tipo I/metabolismo , Animales , Antibacterianos/farmacología , Fiebre Chikungunya/inmunología , Fiebre Chikungunya/veterinaria , Virus Chikungunya/genética , Virus Chikungunya/aislamiento & purificación , Clostridiales/fisiología , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/citología , Monocitos/inmunología , Monocitos/metabolismo , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , ARN Viral/sangre , Factor de Transcripción STAT1/deficiencia , Transducción de Señal , Receptor Toll-Like 7/metabolismoRESUMEN
Natural killer (NK) cells develop from common progenitors but diverge into distinct subsets, which differ in cytokine production, cytotoxicity, homing, and memory traits. Given their promise in adoptive cell therapies for cancer, a deeper understanding of regulatory modules controlling clinically beneficial NK phenotypes is of high priority. We report integrated "-omics" analysis of human NK subsets, which revealed super-enhancers associated with gene cohorts that may coordinate NK functions and localization. A transcription factor-based regulatory scheme also emerged, which is evolutionarily conserved and shared by innate and adaptive lymphocytes. For both NK and T lineages, a TCF1-LEF1-MYC axis dominated the regulatory landscape of long-lived, proliferative subsets that traffic to lymph nodes. In contrast, effector populations circulating between blood and peripheral tissues shared a PRDM1-dominant landscape. This resource defines transcriptional modules, regulated by feedback loops, which may be leveraged to enhance phenotypes for NK cell-based therapies.
Asunto(s)
Células Asesinas Naturales/clasificación , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/fisiología , Citocinas/inmunología , Citocinas/metabolismo , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Humanos , FenotipoRESUMEN
Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8+ and CD4+ T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300ciCre-hCD2R26tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c-traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3CreR26tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c-traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses.
Asunto(s)
Diferenciación Celular , Linaje de la Célula , Células Dendríticas , Animales , Células Dendríticas/inmunología , Ratones , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Análisis de la Célula Individual , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Ratones TransgénicosRESUMEN
Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRß signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion.
Asunto(s)
Neoplasias Encefálicas/inmunología , Puntos de Control del Ciclo Celular , Glioblastoma/inmunología , Células Asesinas Naturales/inmunología , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Animales , Neoplasias Encefálicas/patología , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Femenino , Glioblastoma/patología , Humanos , Inmunidad Innata , Interferón gamma/metabolismo , Células MCF-7 , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor 2 Gatillante de la Citotoxidad Natural/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr-/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr-/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr-/- IELs. Loss of IELs in Ahrr-/- mice caused susceptibility to Clostridium difficile infection and dextran sodium-sulfate-induced colitis. Inflamed tissue of inflammatory bowel disease patients showed reduced Ahrr expression that may contribute to disease. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IELs and to preserve intestinal immune responses.
Asunto(s)
Ferroptosis , Linfocitos Intraepiteliales , Animales , Ratones , Linfocitos Intraepiteliales/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Estrés Oxidativo , HidrocarburosRESUMEN
Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages.
Asunto(s)
Macrófagos , Microglía , Ratones , Animales , Microglía/metabolismo , Macrófagos/metabolismo , Integrasas/genética , Integrasas/metabolismo , Encéfalo/metabolismoRESUMEN
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-ß pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.
Asunto(s)
Enfermedad de Alzheimer/patología , Metabolismo Energético , Glicoproteínas de Membrana/metabolismo , Microglía/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Autofagia , Creatinina/análogos & derivados , Creatinina/metabolismo , Modelos Animales de Enfermedad , Humanos , Lectinas Tipo C/metabolismo , Macrófagos/metabolismo , Glicoproteínas de Membrana/genética , Ratones , Microglía/patología , Neuritas/metabolismo , Placa Amiloide/metabolismo , Receptores Inmunológicos/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Innate lymphoid cells (ILCs) are tissue-resident lymphocytes categorized on the basis of their core regulatory programs and the expression of signature cytokines. Human ILC3s that produce the cytokine interleukin-22 convert into ILC1-like cells that produce interferon-γ in vitro, but whether this conversion occurs in vivo remains unclear. In the present study we found that ILC3s and ILC1s in human tonsils represented the ends of a spectrum that included additional discrete subsets. RNA velocity analysis identified an intermediate ILC3-ILC1 cluster, which had strong directionality toward ILC1s. In humanized mice, the acquisition of ILC1 features by ILC3s showed tissue dependency. Chromatin studies indicated that the transcription factors Aiolos and T-bet cooperated to repress regulatory elements active in ILC3s. A transitional ILC3-ILC1 population was also detected in the human intestine. We conclude that ILC3s undergo conversion into ILC1-like cells in human tissues in vivo, and that tissue factors and Aiolos were required for this process.
Asunto(s)
Inmunidad Innata/inmunología , Interferón gamma/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/inmunología , Linfocitos/inmunología , Tonsila Palatina/inmunología , Animales , Diferenciación Celular/inmunología , Células Cultivadas , Niño , Preescolar , Humanos , Factor de Transcripción Ikaros/metabolismo , Mucosa Intestinal/citología , Linfocitos/clasificación , Linfocitos/citología , Ratones , Proteínas de Dominio T Box/metabolismo , Interleucina-22RESUMEN
Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been extensively studied in model organisms, little is known about these "first responders" in humans, especially their lineage and functional kinships to cytokine-secreting T helper (Th) cell counterparts. Here, we report gene regulatory circuitries for four human ILC-Th counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell-identity genes in each lineage, uncovering new modes of regulation for signature cytokines, new molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILC-Th subsets.
Asunto(s)
Linfocitos/citología , Linfocitos/inmunología , Inmunidad Adaptativa , Animales , Citocinas/inmunología , Citocinas/metabolismo , Elementos de Facilitación Genéticos , Humanos , Inmunidad Innata , Inmunidad Mucosa , Células Asesinas Naturales , Linfocitos/metabolismo , Ratones , Tonsila Palatina/citología , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Factores de Transcripción/metabolismo , TranscriptomaRESUMEN
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment ß-amyloid (Aß) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aß plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aß in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aß accumulation.
Asunto(s)
Glicoproteínas de Membrana/metabolismo , Microglía/metabolismo , Receptores Inmunológicos/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Supervivencia Celular , Modelos Animales de Enfermedad , Humanos , Glicoproteínas de Membrana/genética , Ratones , Microglía/citología , Mutación , Receptores Inmunológicos/genéticaRESUMEN
Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-ß family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-ß family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-ß signaling mediated by the cytokine receptor TGFßR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-ß. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-ß signaling in NK cells.
Asunto(s)
Células Asesinas Naturales/citología , Linfopoyesis/genética , Proteína Smad4/genética , Factor de Crecimiento Transformador beta/inmunología , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/inmunología , Animales , Estudios de Casos y Controles , Diferenciación Celular , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata/inmunología , Immunoblotting , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Linfocitos/citología , Melanoma Experimental/inmunología , Ratones , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunología , Proteína Smad4/inmunologíaRESUMEN
The diversity of natural killer cells between mouse and human is poorly understood. In this issue of Immunity, Crinier et al. (2018) utilize single-cell RNA-seq to profile splenic and blood NK cells from both organisms, uncovering both tissue- and species-specific transcriptomic signatures.
Asunto(s)
Células Asesinas Naturales , Análisis de la Célula Individual , Humanos , Inmunidad , BazoRESUMEN
While signals that activate group 3 innate lymphoid cells (ILC3s) have been described, the factors that negatively regulate these cells are less well understood. Here we found that the tumor necrosis factor (TNF) superfamily member receptor activator of nuclear factor κB ligand (RANKL) suppressed ILC3 activity in the intestine. Deletion of RANKL in ILC3s and T cells increased C-C motif chemokine receptor 6 (CCR6)+ ILC3 abundance and enhanced production of interleukin-17A (IL-17A) and IL-22 in response to IL-23 and during infection with the enteric murine pathogen Citrobacter rodentium. Additionally, CCR6+ ILC3s produced higher amounts of the master transcriptional regulator RORγt at steady state in the absence of RANKL. RANKL-mediated suppression was independent of T cells, and instead occurred via interactions between CCR6+ ILC3s that expressed both RANKL and its receptor, RANK. Thus, RANK-RANKL interactions between ILC3s regulate ILC3 abundance and activation, suggesting that cell clustering may control ILC3 activity.
Asunto(s)
Inmunidad Innata/inmunología , Subgrupos Linfocitarios/inmunología , Ligando RANK/inmunología , Animales , Citocinas/biosíntesis , Citocinas/inmunología , Subgrupos Linfocitarios/metabolismo , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/biosíntesis , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Ligando RANK/metabolismo , Receptores CCR6/inmunologíaRESUMEN
TREM2 is a myeloid cell receptor that has been extensively described in the context of neuroinflammation and neurodegenerative diseases. Recently, TREM2 emerged as a crucial regulator of macrophage function in tumors. TREM2-deficiency or blockade provide protection and promote the response to anti-PD1 in different murine models. In human tumors, TREM2-expressing macrophages are present in numerous cohorts and tumor types and are generally associated with immunosuppression and poor prognosis. Here, we provide an overview of the impact of TREM2 in tumors considering current literature, with a focus on both murine models and human cancer.
Asunto(s)
Enfermedades Neurodegenerativas , Microambiente Tumoral , Humanos , Ratones , Animales , Macrófagos/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Células Mieloides , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/genéticaRESUMEN
Interleukin 22 (IL-22) promotes intestinal barrier integrity, stimulating epithelial cells to enact defense mechanisms against enteric infections, including the production of antimicrobial peptides. IL-22 binding protein (IL-22BP) is a soluble decoy encoded by the Il22ra2 gene that decreases IL-22 bioavailability, attenuating IL-22 signaling. The impact of IL-22BP on gut microbiota composition and functioning is poorly understood. We found that Il22ra2-/- mice are better protected against Clostridioides difficile and Citrobacter rodentium infections. This protection relied on IL-22-induced antimicrobial mechanisms before the infection occurred, rather than during the infection itself. Indeed, the gut microbiota of Il22ra2-/- mice mitigated infection of wild-type (WT) mice when transferred via cohousing or by cecal microbiota transplantation. Indicator species analysis of WT and Il22ra2-/- mice with and without cohousing disclosed that IL22BP deficiency yields a gut bacterial composition distinct from that of WT mice. Manipulation of dietary fiber content, measurements of intestinal short-chain fatty acids and oral treatment with acetate disclosed that resistance to C. difficile infection is related to increased production of acetate by Il22ra2-/--associated microbiota. Together, these findings suggest that IL-22BP represents a potential therapeutic target for those at risk for or with already manifest infection with this and perhaps other enteropathogens.