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At least 19 recordsLinked to original sources
PubMed2012

The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells.

Innate lymphoid cells (ILCs) reside at mucosal surfaces and control immunity to intestinal infections. Type 2 innate lymphoid cells (ILC2s) produce cytokines such as IL-5 and IL-13, are required for immune defense against helminth infections, and are involved in the pathogenesis of airway hyperreactivity. Here, we have investigated the role of the transcription factor GATA-3 for ILC2 differentiation and maintenance. We showed that ILC2s and their lineage-specified bone marrow precursors (ILC2Ps), as identified here, were characterized by continuous high expression of GATA-3. Analysis of mice with temporary deletion of GATA-3 in all ILCs showed that GATA-3 was required for the differentiation and maintenance of ILC2s but not for RORγt(+) ILCs. Thus, our data demonstrate that GATA-3 is essential for ILC2 fate decisions and reveal similarities between the transcriptional programs controlling ILC and T helper cell fates.

Animals↗
PubMed2015

Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets.

The recognized diversity of innate lymphoid cells (ILCs) is rapidly expanding. Three ILC classes have emerged, ILC1, ILC2 and ILC3, with ILC1 and ILC3 including several subsets. The classification of some subsets is unclear, and it remains controversial whether natural killer (NK) cells and ILC1 cells are distinct cell types. To address these issues, we analyzed gene expression in ILCs and NK cells from mouse small intestine, spleen and liver, as part of the Immunological Genome Project. The results showed unique gene-expression patterns for some ILCs and overlapping patterns for ILC1 cells and NK cells, whereas other ILC subsets remained indistinguishable. We identified a transcriptional program shared by small intestine ILCs and a core ILC signature. We revealed and discuss transcripts that suggest previously unknown functions and developmental paths for ILCs.

Animals↗
PubMed2018

E3 Ligase VHL Promotes Group 2 Innate Lymphoid Cell Maturation and Function via Glycolysis Inhibition and Induction of Interleukin-33 Receptor.

Group 2 innate lymphoid cells (ILC2s) are a specialized subset of lymphoid effector cells that are critically involved in allergic responses; however, the mechanisms of their regulation remain unclear. We report that conditional deletion of the E3 ubiquitin ligase VHL in innate lymphoid progenitors minimally affected early-stage bone marrow ILC2s but caused a selective and intrinsic decrease in mature ILC2 numbers in peripheral non-lymphoid tissues, resulting in reduced type 2 immune responses. VHL deficiency caused the accumulation of hypoxia-inducible factor 1α (HIF1α) and attenuated interleukin-33 (IL-33) receptor ST2 expression, which was rectified by HIF1α ablation or inhibition. HIF1α-driven expression of the glycolytic enzyme pyruvate kinase M2 downmodulated ST2 expression via epigenetic modification and inhibited IL-33-induced ILC2 development. Our study indicates that the VHL-HIF-glycolysis axis is essential for the late-stage maturation and function of ILC2s via targeting IL-33-ST2 pathway.

Animals↗
PubMed2025

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.

The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.

Humans↗
PubMed2026

Spatial niche remodeling of senescent liver-resident immune cells and its role in chronic liver diseases.

The liver serves the triple functions of metabolism, detoxification, and immune surveillance. Its unique immune microenvironment is shaped by continuous exposure to gut-derived antigens, pathogen-associated molecular patterns (PAMPs), and metabolites arriving via the portal vein, necessitating a delicate equilibrium between immune tolerance and effector activation. This equilibrium relies on the coordinated activities of diverse liver-resident immune cell populations-including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), dendritic cells (DCs), tissue-resident memory T cells (TRM), innate-like T cells, including mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδ T cells, innate lymphoid cells (ILCs, encompassing conventional NK cells and helper ILC subsets), and neutrophils. With advancing age and chronic injury, these resident immune cell populations undergo profound senescence-associated phenotypic reprogramming that is spatially organized along the portal-to-central axis of the hepatic lobule. Key mechanisms include: telomere dysfunction and DNA damage accumulation driving persistent activation of p53/p21 and p16/Rb pathways; mitochondrial dysfunction with mitochondrial DNA (mtDNA) leakage fueling the senescence-associated secretory phenotype (SASP) via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; epigenetic age acceleration, including genome-wide H3K27me3 heterochromatinization; and metabolic reprogramming toward glycolysis and lipid accumulation. This review proposes a "spatial niche remodeling" framework to integrate these cell-intrinsic senescence programs with their lobular context, intercellular communication network rewiring, and pathogenic roles across the spectrum of chronic liver disease-from steatosis through steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. We critically evaluate emerging senotherapeutic strategies targeting specific liver-resident immune cell subsets, discuss the barriers to clinical translation, and identify priority areas for future investigation, including the application of spatial multi-omics, humanized models, and epigenetic clock-guided clinical trials.

Kupffer cells↗
PubMed2002

Having it all? Stem cells, haematopoiesis and lymphopoiesis in adult human liver.

Because of its location and function, the liver is continuously exposed to large antigenic loads that include pathogens, toxins and tumour cells, as well as harmless dietary and commensal proteins and peptides. Therefore, the liver must be actively immunocompetent and, at the same time, control inappropriate inflammatory responses to dietary and other harmless antigens encountered in the portal circulation. In addition to conventional CD4+ and CD8+ T lymphocytes from the circulation, several specialized lymphoid populations are found in the liver to meet these diverse immunological challenges. These populations display the functional and phenotypic properties of innate cells as well as conventional CD4+ or CD8+ helper and cytotoxic T lymphocytes and B cells. The innate lymphoid cells include gammadeltaTCR+ T cells, B1-B cells and NKT cells as well as large numbers of NK cells. The origin of these cells is unknown, but their murine counterparts have been shown to be capable of differentiation in situ in adult liver. Because haematopoietic stem cells have been found in adult human liver as well as molecular evidence of T-cell maturation, we hypothesize that some resident human hepatic lymphoid cells, particularly those expressing innate phenotypes, also differentiate locally. In particular, it is likely that the adult human liver is an important site of NK cell maturation. In this review, we explore the evidence for an active lymphopoietic role for the normal adult human liver.

Adult↗
PubMed2026

Ascites reprograms innate lymphoid immune cells in ovarian cancer by promoting ILC2 enrichment and dysfunctional NK-cell states.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is commonly accompanied by malignant ascites, a clinically relevant tumor niche that promotes immune evasion, metastasis, and treatment resistance. Although natural killer (NK)-cell dysfunction has been described in ovarian cancer, the broader innate lymphoid landscape of ascites and the mechanisms linking ascites-derived signals to innate immune suppression remain insufficiently resolved. METHODS: We performed single-cell RNA sequencing of NK/innate lymphoid cells from ovarian cancer ascites to define cellular heterogeneity and differentiation states. Functional assays assessed NK-cell cytotoxicity, degranulation, and receptor expression following exposure to patient-derived ascites, with or without transforming growth factor-β (TGF-β) receptor inhibition. Proteomic profiling was used to characterize the soluble ascites milieu, and clinical associations were examined for innate lymphoid subsets. RESULTS: Single-cell analysis identified eight transcriptionally distinct NK/innate lymphoid states, including cytotoxic, precursor, early-like, tolerant/immunoregulatory, regulatory, proinflammatory, and innate lymphoid populations. Ovarian cancer ascites was characterized by depletion of cytotoxic and precursor NK-cell states together with enrichment of early-like, tolerant, regulatory, pro-inflammatory, and innate lymphoid cell (ILC) populations. Trajectory analysis indicated impaired maturation toward terminally differentiated cytotoxic NK cells. Notably, ascites contained an expanded population of programmed cell death protein 1 (PD-1)+ ILC2s, which were more abundant in patients with shorter progression-free survival. In functional assays, short-term exposure of healthy donor NK cells to ascites suppressed degranulation and tumor-cell killing, reduced expression of activating receptors including NKp30 and DNAM-1, increased inhibitory receptor expression, and shifted NK cells toward a CD56highCD16low phenotype. Proteomic profiling supported a soluble milieu consistent with type 2 immune skewing and NK-cell suppression. Importantly, TGF-β receptor inhibition partially restored NK-cell activation and function in the presence of ascites. CONCLUSIONS: HGSOC ascites establishes a type 2-skewed immunoregulatory niche that coordinately drives NK cell dysfunction and PD-1+ ILC2 accumulation. The findings identify TGF-β-linked suppression and ascites-associated immune regulators as candidate immunotherapeutic vulnerabilities for restoring antitumor immunity in ovarian cancer.

Humans↗
PubMed2025

Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy.

Hepatocellular carcinoma (HCC) is an increasingly prevalent and deadly disease that is initiated by different etiological factors, such as alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatohepatitis (MASH), viral hepatitis, and other hepatotoxic and hepatocarcinogenic agents. The tumor microenvironment (TME) of HCC is characterized by several different fibroblastic and immune cell types, all of which affect the initiation, progression and metastasis of this malignant cancer. This complex immune TME can be divided into an innate component that includes macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, mucosal-associated invariant T cells, natural killer cells, natural killer T cells, and innate lymphoid cells, as well as an adaptive component that includes CD4+ T cells, CD8+ T cells, regulatory T cells, and B cells. In this review, we discuss the latest findings shedding light on the direct or indirect roles of these immune cells (and fibroblastic-like cells such as hepatic stellate cells) in the pathogenesis of HCC. Henceforth, further characterization of this heterogeneous TME is highly important for studying the progression of HCC and developing novel immunotherapeutic treatment options. In line with this, we also review novel groundbreaking experimental techniques and animal models aimed at specifically elucidating this complex TME and discuss emerging immune-based therapeutic strategies intended to treat HCC and predict the efficacy of these immunotherapies.

Humans↗
PubMed2025

DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.

Adolescent↗
PubMed2023

Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils.

BACKGROUND: Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy. METHODS: The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans. RESULTS: Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy. CONCLUSION: Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

Mice↗
PubMed2024

Tuft cell acetylcholine is released into the gut lumen to promote anti-helminth immunity.

Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function.

Animals↗
PubMed2026

Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming.

Pulmonary group 2 innate lymphoid cells (ILC2s) are key drivers of Type 2 inflammation in diseases like asthma, yet the molecular mechanisms regulating their function are incompletely understood. Using the genetically diverse Collaborative Cross (CC) mouse panel, we mapped a quantitative trait locus (QTL) that governs ILC2 prevalence in the lung after aeroallergen exposure. This QTL induces a large population of ILC2s in the lung that are resistant to activation and have diminished Type 2 effector function. We identified free-fatty acid receptor 3 (Ffar3) as a gene responsible for this effect and demonstrated that FFAR3 signaling reprograms ILC2s to an anti-inflammatory state by promoting their survival, reducing Type 2 cytokine production, and enhancing IL-10 expression. This anti-inflammatory state is dependent on IL-2 signaling, is characterized by decreased ST2 expression, and is distinct from previously described IL-10-producing ILC2 phenotypes. FFAR3-dependent reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation, and FFAR3's anti-inflammatory effect is partially conserved in human ILC2s.

Animals↗
PubMed2000

Innate and adaptive lymphoid cells in the human liver.

Because of its location and function, the liver is continuously exposed to a large antigenic load that includes pathogens, toxins, tumor cells and harmless dietary antigens. The range of local immune mechanisms required to cope with this diverse immunological challenge is now being appreciated. The liver has an "epithelial constitution" and contains large numbers of phagocytic cells, antigen-presenting cells and lymphocytes and is a site for the production of cytokines, complement components and acute phase proteins. In this review, we focus on the hepatic lymphoid system, which is currently emerging as an important arm of the immune system in the liver for targeting pathogens as well as for the recognition of cells that are modified as a result of infection or tumor transformation. We show that this organ contains a heterogeneity of lymphoid cells with diverse recognition mechanisms and functions. There are conventional T lymphocytes that use clonotypic receptors to identify and respond to antigenic peptides presented in the context of polymorphic class I and class II major histocompatibilty complex (MHC) molecules. But these cells are outnumbered by lymphoid cells that recognize common structures using receptors with limited diversity. These mediators of innate immunity against infectious pathogens and malignant cells respond immediately to stimuli and function as a temporal (and perhaps evolutionary) bridge for the adaptive immune response.

Acute-Phase Proteins↗
PubMed1998

Natural killer and T cells of innate and adaptive immunity: lymphoid compartments with different requirements for common gamma chain-dependent cytokines.

A group of cytokines, including interleukin-2, -4, -7, -9 and -15, are related through the usage of a shared receptor subunit, the common cytokine receptor gamma chain, gamma c. gamma c-dependent cytokines critically affect the development and maintenance of the lymphoid system. This review will highlight our current knowledge on the gamma c-dependent cytokine network and on the non-redundant roles that these cytokines play in the development and homeostasis of T and natural killer cells involved in innate and adaptive immunity.

Animals↗
PubMed2025

Refined cell transfer model reveals roles for Ascl2 and Cxcr3 in splenic localization of mouse NK cells during virus infection.

Cell transfer experiments complement the rigorous investigation of antiviral and antitumor functions of natural killer (NK) cells. Success in these endeavors is enhanced by expansion of small numbers of input NK cells driven by viral antigens or homeostatic proliferation in immunodeficient hosts. In contrast, analysis of other NK-cell functions, including immunoregulation, are non-proliferative and require an intact immune system in recipient mice. We reveal poor persistence of conventional congenic (CD45.1) BoyJ NK cells following adoptive transfer in comparison to CRISPR-generated CD45.1+ (JAXBoy) NK cells. Reciprocal transfers between C57BL/6 and JAXBoy mice substantially improve seeding and maintenance of donor NK cells. Using this system, we confirm that CXCR3 re-positions NK cells in the white pulp of the spleen after infection, which is vital for immunoregulation. Moreover, we discovered that the transcription factor ASCL2 is required for recruitment of NK cells into the spleen and white pulp. These results provide improved tools and novel insights into NK cell biology.

Animals↗
PubMed2006

Dynamic imaging of the immune system: progress, pitfalls and promise.

Both innate and adaptive immunity are dependent on the migratory capacity of myeloid and lymphoid cells. Effector cells of the innate immune system rapidly enter infected tissues, whereas sentinel dendritic cells in these sites mobilize and transit to lymph nodes. In these and other secondary lymphoid tissues, interactions among various cell types promote adaptive humoral and cell-mediated immune responses. Recent advances in light microscopy have allowed direct visualization of these events in living animals and tissue explants, which allows a new appreciation of the dynamics of immune-cell behaviour. In this article, we review the basic techniques and the tools used for in situ imaging, as well as the limitations and potential artefacts of these methods.

Animals↗
PubMed2006

Innate immune response to human bone marrow fibroblastic cell implantation in CB17 scid/beige mice.

Immunocompromised mouse models have been extensively used to assess human cell implantation for evaluation of cytotherapy, gene therapy and tissue engineering strategies, as these mice are deficient in T and B lymphoid cells. However, the innate immune response and its effect on human cell xenotransplantation in these mouse models are mainly unknown. The aim of this study is to characterise the myeloid populations in the spleen and blood of CB17 scid beige (CB17 sb) mice, and to study the inflammatory cell responses to xenogeneic implantation of enhanced green fluorescent protein (GFP)-labelled human bone marrow fibroblastic (HBMF) cells into CB17 sb mice. The results indicate that even though CB17 sb mice are deficient in B- and T-cells, they exhibit some increases in their monocyte (Mo), macrophage (Mphi) and neutrophil (Neu) populations. NK cell and eosinophil populations show no differences compared with wild-type Balb/C mice. An innate immune response, identified by CR3 (CD11b/CD18)-positive myeloid inflammatory cells and F4/80-positive macrophages, was evident in the tissues where HBMF cells were implanted. As a consequence, the majority of implanted HBMF cells were eliminated by 4 weeks after implantation. Interestingly, the mineralised matrix formed by osteogenic HBMF cells was also eroded by multinuclear Mphi-like giant cells. We conclude that CB17 sb mice retain active innate immune cells, which respond to HBMF cell xenotransplantation. This study highlights the importance of the innate immune cells in the anti-xenograft response and suggests that strategies to block the activities of these cells may ameliorate the progressive long-term elimination of xenotransplants.

Animals↗