RESUMEN
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
BACKGROUND & AIMS: The pathophysiology of Crohn's-like disease of the ileal pouch-anal anastomosis (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single cell analyses. METHODS: Endoscopic samples were collected from pouch body and pre-pouch ileum (pouch/ileum) of 50 patients with an IPAA. Single-cell RNA sequencing (scRNA-seq) was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, as well as those with familial adenomatous polyposis (FAP) after pouch formation. Findings were independently validated using immunohistochemistry. RESULTS: The cell populations/states in pouch body differed from those in pre-pouch ileum, likely secondary to increased microbial burden. Compared to FAP pouch, UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in Th17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1+ monocytes, clonal expansion of effector T cells, and overexpression of Th17-inducing cytokine genes such as IL23, IL1B and IL6 by mononuclear phagocytes (MNPs). Ligand-receptor analysis further revealed a stromal-MNP-lymphocyte circuit in CDP. Integrated analysis showed that upregulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum (ER) stress across all major cell compartments. CONCLUSIONS: CDP likely represents a distinct entity of inflammatory bowel disease with heightened ER stress in both immune and non-immune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP.
RESUMEN
Recent advances in human genetics have shed light on the genetic factors contributing to inflammatory diseases, particularly Crohn's disease (CD), a prominent form of inflammatory bowel disease. Certain risk genes associated with CD directly influence cytokine biology and cell-specific communication networks. Current CD therapies primarily rely on anti-inflammatory drugs, which are inconsistently effective and lack strategies for promoting epithelial restoration and mucosal balance. To understand CD's underlying mechanisms, we investigated the link between CD and the FGFR1OP gene, which encodes a centrosome protein. FGFR1OP deletion in mouse intestinal epithelial cells disrupted crypt architecture, resulting in crypt loss, inflammation, and fatality. FGFR1OP insufficiency hindered epithelial resilience during colitis. FGFR1OP was crucial for preserving non-muscle myosin II activity, ensuring the integrity of the actomyosin cytoskeleton and crypt cell adhesion. This role of FGFR1OP suggests that its deficiency in genetically predisposed individuals may reduce epithelial renewal capacity, heightening susceptibility to inflammation and disease.
RESUMEN
The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.
Asunto(s)
Microbioma Gastrointestinal , Inmunoterapia , Macrófagos , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1 , Receptores Inmunológicos , Animales , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Ratones , Microbioma Gastrointestinal/inmunología , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Macrófagos/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Ratones Noqueados , Femenino , Intestinos/inmunologíaRESUMEN
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.
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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
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.
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Citrobacter rodentium , Clostridioides difficile , Infecciones por Enterobacteriaceae , Microbioma Gastrointestinal , Interleucina-22 , Ratones Noqueados , Animales , Ratones , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/prevención & control , Receptores de Interleucina/metabolismo , Receptores de Interleucina/genética , Interleucinas/metabolismo , Ratones Endogámicos C57BL , Infecciones por Clostridium/inmunología , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/prevención & controlRESUMEN
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.
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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
NKp44 is a human receptor originally found on activated NK cells, group 1 and group 3 innate lymphoid cells that binds dimers of platelet-derived growth factor D (PDGF-DD). NKp44 is also expressed on tissue plasmacytoid dendritic cells (PDCs), but NKp44-PDGF-DD interaction on PDCs remains unstudied. Engagement of NKp44 with PDGF-DD in vitro enhanced PDC secretion of IFN-α, TNF, and IL-6 in response to the TLR9 ligand CpG-ODN, but not TLR7/8 ligands. In tissues, PDCs were found in close contact with PDGF-DD-expressing cells in the high endothelial venules and epithelium of tonsils, melanomas, and skin lesions infected with Molluscum contagiosum. Recombinant PDGF-DD enhanced the serum IFN-α response to systemic HSV-1 infection in a humanized mouse model. We conclude that NKp44 integrates with TLR9 signaling to enhance PDC cytokine production. These findings may have bearings for immune responses to TLR9-based adjuvants, therapy for tumors expressing PDGF-DD, and infections with DNA viruses that induce PDGF-DD expression to enhance viral spread.
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Inmunidad Innata , Receptor Toll-Like 9 , Animales , Ratones , Humanos , Receptor Toll-Like 9/metabolismo , Interferón-alfa/metabolismo , Células Dendríticas , Células Asesinas NaturalesRESUMEN
Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt+ MHCII+ type 3 innate lymphoid cells (ILC3) have also been implicated in the instruction of microbiota-specific Tregs. While RORγt+ APCs have been actively investigated in mice, the identity and function of these cell subsets in humans remain elusive. Herein, we identify a rare subset of RORγt+ cells with dendritic cell (DC) features through integrated single-cell RNA sequencing and single-cell ATAC sequencing. These cells, which we term RORγt+ DC-like cells (R-DC-like), exhibit DC morphology, express the MHC class II machinery, and are distinct from all previously reported DC and ILC3 subsets, but share transcriptional and epigenetic similarities with DC2 and ILC3. We have developed procedures to isolate and expand them in vitro, enabling their functional characterization. R-DC-like cells proliferate in vitro, continue to express RORγt, and differentiate into CD1c+ DC2-like cells. They stimulate the proliferation of allogeneic T cells. The identification of human R-DC-like cells with proliferative potential and plasticity toward CD1c+ DC2-like cells will prompt further investigation into their impact on immune homeostasis, inflammation, and autoimmunity.
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Inmunidad Innata , Linfocitos , Humanos , Ratones , Animales , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Inflamación/metabolismo , Células DendríticasRESUMEN
TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.
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Enfermedad de Alzheimer , Microglía , Adulto , Humanos , Microglía/metabolismo , Metabolismo de los Lípidos/genética , Mutación con Pérdida de Función , Mutación/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Lisosomas/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptor de ProreninaRESUMEN
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.
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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
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.
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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.
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Macrófagos , Microglía , Ratones , Animales , Microglía/metabolismo , Macrófagos/metabolismo , Integrasas/genética , Integrasas/metabolismo , Encéfalo/metabolismoRESUMEN
Group 2 innate lymphoid cells (ILC2) are innate counterparts of T helper 2 (Th2) cells that maintain tissue homeostasis and respond to injuries through rapid interleukin (IL)-5 and IL-13 secretion. ILC2s depend on availability of arginine and branched-chain amino acids for sustaining cellular fitness, proliferation, and cytokine secretion in both steady state and upon activation. However, the contribution of amino acid transporters to ILC2 functions is not known. Here, we found that ILC2s selectively express Slc7a8, encoding a transporter for arginine and large amino acids. Slc7a8 was expressed in ILC2s in a tissue-specific manner in steady state and was further increased upon activation. Genetic ablation of Slc7a8 in lymphocytes reduced the frequency of ILC2s, suppressed IL-5 and IL-13 production upon stimulation, and impaired type 2 immune responses to helminth infection. Consistent with this, Slc7a8-deficient ILC2s also failed to induce cytokine production and recruit eosinophils in a model of allergic lung inflammation. Mechanistically, reduced amino acid availability due to Slc7a8 deficiency led to compromised mitochondrial oxidative phosphorylation, as well as impaired activation of mammalian target of rapamycin and c-Myc signaling pathways. These findings identify Slc7a8 as a key supplier of amino acids for the metabolic programs underpinning fitness and activation of ILC2s.
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Inmunidad Innata , Linfocitos , Interleucina-13/genética , Aminoácidos , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal , Homeostasis , Arginina , Citocinas/metabolismo , Interleucina-33 , Pulmón/metabolismoRESUMEN
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.
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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
The role of NK cells against HIV-1 infections remains to be elucidated in vivo. While humanized mouse models potentially could be used to directly evaluate human NK cell responses during HIV-1 infection, improved functional development of human NK cells in these hosts is needed. Here, we report the humanized MISTRG-6-15 mouse model, in which NK cells were quick to expand and exhibit degranulation, cytotoxicity, and proinflammatory cytokine production in nonlymphoid organs upon HIV-1 infection but had reduced functionality in lymphoid organs. Although HIV-1 infection induced functional impairment of NK cells, antiretroviral therapy reinvigorated NK cells in response to HIV-1 rebound after analytic treatment interruption. Moreover, a broadly neutralizing antibody, PGT121, enhanced NK cell function in vivo, consistent with antibody-dependent cellular cytotoxicity. Monoclonal antibody depletion of NK cells resulted in higher viral loads in multiple nonlymphoid organs. Overall, our results in humanized MISTRG-6-15 mice demonstrated that NK cells provided direct anti-HIV-1 responses in vivo but were limited in their responses in lymphoid organs.
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Infecciones por VIH , VIH-1 , Humanos , Ratones , Animales , Citotoxicidad Celular Dependiente de Anticuerpos , Carga Viral , Células Asesinas NaturalesRESUMEN
C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α− conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4− eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.
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Eosinófilos , Receptores de Hidrocarburo de Aril , Receptores de Superficie Celular , Eosinofilia/terapia , Hipersensibilidad a los Alimentos/terapia , Inmunomodulación , Intestino Delgado , Recuento de Leucocitos , Ligandos , Receptores de Hidrocarburo de Aril/genéticaRESUMEN
Identification of type 1 innate lymphoid cells (ILC1s) has been problematic. The transcription factor Hobit encoded by Zfp683 has been proposed as a major driver of ILC1 programs. Using Zfp683 reporter mice, we showed that correlation of Hobit expression with ILC1s is tissue- and context-dependent. In liver and intestinal mucosa, Zfp683 expression correlated well with ILC1s; in salivary glands, Zfp683 was coexpressed with the natural killer (NK) master transcription factors Eomes and TCF1 in a unique cell population, which we call ILC1-like NK cells; during viral infection, Zfp683 was induced in conventional NK cells of spleen and liver. The impact of Zfp683 deletion on ILC1s and NK cells was also multifaceted, including a marked decrease in granzyme- and interferon-gamma (IFNγ)-producing ILC1s in the liver, slightly fewer ILC1s and more Eomes+ TCF1+ ILC1-like NK cells in salivary glands, and only reduced production of granzyme B by ILC1 in the intestinal mucosa. NK cell-mediated control of viral infection was unaffected. We conclude that Hobit has two major impacts on ILC1s: It sustains liver ILC1 numbers, while promoting ILC1 functional maturation in other tissues by controlling TCF1, Eomes, and granzyme expression.