ABSTRACT
Over the last decade, immunometabolism has emerged as a novel interdisciplinary field of research and yielded significant fundamental insights into the regulation of immune responses. Multiple classical approaches to interrogate immunometabolism, including bulk metabolic profiling and analysis of metabolic regulator expression, paved the way to appreciating the physiological complexity of immunometabolic regulation in vivo. Studying immunometabolism at the systems level raised the need to transition towards the next-generation technology for metabolic profiling and analysis. Spatially resolved metabolic imaging and computational algorithms for multi-modal data integration are new approaches to connecting metabolism and immunity. In this review, we discuss recent studies that highlight the complex physiological interplay between immune responses and metabolism and give an overview of technological developments that bear the promise of capturing this complexity most directly and comprehensively.
Subject(s)
Allergy and Immunology , Immunity , Metabolism , Animals , Humans , Systems BiologyABSTRACT
Tumor angiogenesis and immunity show an inverse correlation in cancer progression and outcome1. Here, we report that ZBTB46, a repressive transcription factor and a widely accepted marker for classical dendritic cells (DCs)2,3, controls both tumor angiogenesis and immunity. Zbtb46 was downregulated in both DCs and endothelial cells by tumor-derived factors to facilitate robust tumor growth. Zbtb46 downregulation led to a hallmark pro-tumor microenvironment (TME), including dysfunctional vasculature and immunosuppressive conditions. Analysis of human cancer data revealed a similar association of low ZBTB46 expression with an immunosuppressive TME and a worse prognosis. In contrast, enforced Zbtb46 expression led to TME changes to restrict tumor growth. Mechanistically, Zbtb46-deficient endothelial cells were highly angiogenic, and Zbtb46-deficient bone marrow progenitors upregulated Cebpb and diverted the DC program to immunosuppressive myeloid lineage output, potentially explaining the myeloid lineage skewing phenomenon in cancer4. Conversely, enforced Zbtb46 expression normalized tumor vessels and, by suppressing Cebpb, skewed bone marrow precursors toward immunostimulatory myeloid lineage output, leading to an immune-hot TME. Remarkably, Zbtb46 mRNA treatment synergized with anti-PD1 immunotherapy to improve tumor management in preclinical models. These findings identify ZBTB46 as a critical factor for angiogenesis and for myeloid lineage skewing in cancer and suggest that maintaining its expression could have therapeutic benefits.
ABSTRACT
The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-ß signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.
Subject(s)
Dementia , Subacute Sclerosing Panencephalitis , Animals , Humans , Mice , Brain/metabolism , Dementia/metabolism , Dementia/pathology , Membrane Glycoproteins/metabolism , Microglia/metabolism , Receptors, Immunologic/metabolism , Subacute Sclerosing Panencephalitis/metabolism , Subacute Sclerosing Panencephalitis/pathologyABSTRACT
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a global cause of death. Granuloma-associated lymphoid tissue (GrALT) correlates with protection during TB, but the mechanisms of protection are not understood. During TB, the transcription factor IRF4 in T cells but not B cells is required for the generation of the TH1 and TH17 subsets of helper T cells and follicular helper T (TFH)-like cellular responses. A population of IRF4+ T cells coexpress the transcription factor BCL6 during Mtb infection, and deletion of Bcl6 (Bcl6fl/fl) in CD4+ T cells (CD4cre) resulted in reduction of TFH-like cells, impaired localization within GrALT and increased Mtb burden. In contrast, the absence of germinal center B cells, MHC class II expression on B cells, antibody-producing plasma cells or interleukin-10-expressing B cells, did not increase Mtb susceptibility. Indeed, antigen-specific B cells enhance cytokine production and strategically localize TFH-like cells within GrALT via interactions between programmed cell death 1 (PD-1) and its ligand PD-L1 and mediate Mtb control in both mice and macaques.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Mice , Animals , T-Lymphocytes, Helper-Inducer , B-Lymphocytes , Lymphoid Tissue , Germinal Center , Transcription FactorsABSTRACT
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.
Subject(s)
Immunotherapy , Membrane Glycoproteins/metabolism , Neoplasms/therapy , Programmed Cell Death 1 Receptor/immunology , Receptors, Immunologic/metabolism , Animals , Antibodies, Monoclonal/therapeutic use , CX3C Chemokine Receptor 1/metabolism , Cell Line, Tumor , Disease Models, Animal , Humans , Lymphocytes, Tumor-Infiltrating/cytology , Lymphocytes, Tumor-Infiltrating/metabolism , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Methylcholanthrene/toxicity , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/chemically induced , Neoplasms/pathology , Prognosis , Programmed Cell Death 1 Receptor/metabolism , Receptors, Immunologic/deficiency , Receptors, Immunologic/genetics , Tumor MicroenvironmentABSTRACT
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.
Subject(s)
Bile Acids and Salts/metabolism , Chikungunya Fever/pathology , Gastrointestinal Microbiome , Interferon Type I/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Chikungunya Fever/immunology , Chikungunya Fever/veterinary , Chikungunya virus/genetics , Chikungunya virus/isolation & purification , Clostridiales/physiology , Dendritic Cells/cytology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Fecal Microbiota Transplantation , Gastrointestinal Microbiome/drug effects , Male , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Myeloid Differentiation Factor 88/deficiency , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , RNA, Viral/blood , STAT1 Transcription Factor/deficiency , Signal Transduction , Toll-Like Receptor 7/metabolismABSTRACT
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5'-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, we show that fasting improves chronic inflammatory diseases without compromising monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
Subject(s)
Caloric Restriction , Monocytes/metabolism , AMP-Activated Protein Kinases/metabolism , Adult , Animals , Antigens, Ly/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Chemokine CCL2/deficiency , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Female , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , Inflammation/metabolism , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/cytology , PPAR alpha/deficiency , PPAR alpha/genetics , PPAR alpha/metabolismABSTRACT
Although current immune-checkpoint therapy (ICT) mainly targets lymphoid cells, it is associated with a broader remodeling of the tumor micro-environment. Here, using complementary forms of high-dimensional profiling, we define differences across all hematopoietic cells from syngeneic mouse tumors during unrestrained tumor growth or effective ICT. Unbiased assessment of gene expression of tumor-infiltrating cells by single-cell RNA sequencing (scRNAseq) and longitudinal assessment of cellular protein expression by mass cytometry (CyTOF) revealed significant remodeling of both the lymphoid and myeloid intratumoral compartments. Surprisingly, we observed multiple subpopulations of monocytes/macrophages, distinguishable by the markers CD206, CX3CR1, CD1d, and iNOS, that change over time during ICT in a manner partially dependent on IFNγ. Our data support the hypothesis that this macrophage polarization/activation results from effects on circulatory monocytes and early macrophages entering tumors, rather than on pre-polarized mature intratumoral macrophages.
Subject(s)
Lymphocytes/immunology , Myeloid Cells/immunology , Neoplasms/immunology , Single-Cell Analysis , Transcriptome , Animals , Cell Line, Tumor , Flow Cytometry , Immunotherapy/methods , Interferon-gamma/immunology , Macrophage Activation , Male , Mass Spectrometry , Mice , Monocyte-Macrophage Precursor Cells/immunology , Neoplasms/therapyABSTRACT
Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DCs) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage-tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aortic intima resident macrophages (MacAIR) that depend upon colony-stimulating factor 1 and are sustained by local proliferation. Although MacAIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaques is overtaken by recruited monocytes, which induce MacAIR-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.
Subject(s)
Aorta/immunology , Macrophages/immunology , Monocytes/immunology , Plaque, Atherosclerotic/immunology , Tunica Intima/immunology , Animals , Cell Differentiation , Cell Lineage , Cell Movement , Cell Proliferation , Cells, Cultured , Cholesterol/metabolism , Disease Progression , Humans , Macrophage Colony-Stimulating Factor/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Parabiosis , PhagocytosisABSTRACT
Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the systematic understanding of human aging. Here, using single-cell RNA/T cell receptor (TCR)/BCR-seq with protein feature barcoding, we profiled 317 samples from 166 healthy individuals aged 25-85 years old. From this, we generated a dataset from â¼2 million cells that described 55 subpopulations of blood immune cells. Twelve subpopulations changed with age, including the accumulation of GZMK+CD8+ T cells and HLA-DR+CD4+ T cells. In contrast to other T cell memory subsets, transcriptionally distinct NKG2C+GZMB-CD8+ T cells counterintuitively decreased with age. Furthermore, we found a concerted age-associated increase in type 2/interleukin (IL)4-expressing memory subpopulations across CD4+ and CD8+ T cell compartments (CCR4+CD8+ Tcm and Th2 CD4+ Tmem), suggesting a systematic functional shift in immune homeostasis with age. Our work provides novel insights into healthy human aging and a comprehensive annotated resource.
Subject(s)
CD8-Positive T-Lymphocytes , Memory T Cells , Humans , Adult , Middle Aged , Aged , Aged, 80 and over , T-Lymphocyte Subsets , Aging , Receptors, Antigen, T-Cell/metabolism , Granzymes/metabolismABSTRACT
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.
Subject(s)
Alzheimer Disease/pathology , Energy Metabolism , Membrane Glycoproteins/metabolism , Microglia/metabolism , Receptors, Immunologic/metabolism , AMP-Activated Protein Kinases/metabolism , Alzheimer Disease/metabolism , Animals , Autophagy , Creatinine/analogs & derivatives , Creatinine/metabolism , Disease Models, Animal , Humans , Lectins, C-Type/metabolism , Macrophages/metabolism , Membrane Glycoproteins/genetics , Mice , Microglia/pathology , Neurites/metabolism , Plaque, Amyloid/metabolism , Receptors, Immunologic/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state and expand during type 2 immunity. Whether shared mechanisms regulate the proliferation of macrophages in homeostasis and disease is unclear. Here we found that the transcription factor Bhlhe40 was required in a cell-intrinsic manner for the self-renewal and maintenance of large peritoneal macrophages (LPMs), but not that of other tissue-resident macrophages. Bhlhe40 was necessary for the proliferation, but not the polarization, of LPMs in response to the cytokine IL-4. During infection with the helminth Heligmosomoides polygyrus bakeri, Bhlhe40 was required for cell cycling of LPMs. Bhlhe40 repressed the expression of genes encoding the transcription factors c-Maf and Mafb and directly promoted expression of transcripts encoding cell cycle-related proteins to enable the proliferation of LPMs. In LPMs, Bhlhe40 bound to genomic sites co-bound by the macrophage lineage-determining factor PU.1 and to unique sites, including Maf and loci encoding cell-cycle-related proteins. Our findings demonstrate a tissue-specific control mechanism that regulates the proliferation of resident macrophages in homeostasis and type 2 immunity.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Homeodomain Proteins/genetics , Homeostasis/genetics , Homeostasis/immunology , Immunity/genetics , Macrophages/immunology , Macrophages/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Biomarkers , Cell Cycle/genetics , Cell Cycle/immunology , Cell Proliferation , Gene Expression Profiling , Gene Expression Regulation , Gene Knockout Techniques , Helicobacter Infections/genetics , Helicobacter Infections/immunology , Helicobacter pylori/immunology , Homeodomain Proteins/metabolism , Immunophenotyping , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Mice , Mice, Transgenic , Monocytes/immunology , Monocytes/metabolism , Organ Specificity/genetics , Organ Specificity/immunology , TranscriptomeABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
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.
Subject(s)
Immunity, Innate/immunology , Interferon-gamma/metabolism , Interleukins/metabolism , Intestinal Mucosa/immunology , Lymphocytes/immunology , Palatine Tonsil/immunology , Animals , Cell Differentiation/immunology , Cells, Cultured , Child , Child, Preschool , Humans , Ikaros Transcription Factor/metabolism , Intestinal Mucosa/cytology , Lymphocytes/classification , Lymphocytes/cytology , Mice , T-Box Domain Proteins/metabolism , Interleukin-22ABSTRACT
Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8+ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK+CD8+ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK+ Taa cells as a potential target to address age-associated dysfunctions of the immune system.
Subject(s)
Aging/physiology , CD8-Positive T-Lymphocytes/physiology , Immune System/physiology , Inflammation/immunology , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, T-Cell/genetics , Animals , Cells, Cultured , Clone Cells , Cytotoxicity, Immunologic , Female , Gene Expression Profiling , Granzymes/metabolism , Humans , Immunologic Memory , Mice , Mice, Inbred C57BL , Sequence Analysis, RNA , Single-Cell Analysis , TranscriptomeABSTRACT
During development, inflammation or tissue injury, macrophages may successively engulf and process multiple apoptotic corpses via efferocytosis to achieve tissue homeostasis1. How macrophages may rapidly adapt their transcription to achieve continuous corpse uptake is incompletely understood. Transcriptional pause/release is an evolutionarily conserved mechanism, in which RNA polymerase (Pol) II initiates transcription for 20-60 nucleotides, is paused for minutes to hours and is then released to make full-length mRNA2. Here we show that macrophages, within minutes of corpse encounter, use transcriptional pause/release to unleash a rapid transcriptional response. For human and mouse macrophages, the Pol II pause/release was required for continuous efferocytosis in vitro and in vivo. Interestingly, blocking Pol II pause/release did not impede Fc receptor-mediated phagocytosis, yeast uptake or bacterial phagocytosis. Integration of data from three genomic approaches-precision nuclear run-on sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-seq)-on efferocytic macrophages at different time points revealed that Pol II pause/release controls expression of select transcription factors and downstream target genes. Mechanistic studies on transcription factor EGR3, prominently regulated by pause/release, uncovered EGR3-related reprogramming of other macrophage genes involved in cytoskeleton and corpse processing. Using lysosomal probes and a new genetic fluorescent reporter, we identify a role for pause/release in phagosome acidification during efferocytosis. Furthermore, microglia from egr3-deficient zebrafish embryos displayed reduced phagocytosis of apoptotic neurons and fewer maturing phagosomes, supporting defective corpse processing. Collectively, these data indicate that macrophages use Pol II pause/release as a mechanism to rapidly alter their transcriptional programs for efficient processing of the ingested apoptotic corpses and for successive efferocytosis.
Subject(s)
Efferocytosis , Macrophages , RNA Polymerase II , Transcription Elongation, Genetic , Animals , Humans , Male , Mice , Apoptosis , Cytoskeleton/metabolism , Early Growth Response Protein 3/deficiency , Early Growth Response Protein 3/genetics , Efferocytosis/genetics , Hydrogen-Ion Concentration , Macrophages/immunology , Macrophages/metabolism , Neurons/metabolism , Phagosomes/metabolism , RNA Polymerase II/metabolism , Transcription Factors/genetics , Zebrafish/embryology , Zebrafish/genetics , Time FactorsABSTRACT
CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.
Subject(s)
Antigens, Neoplasm , CD4-Positive T-Lymphocytes , Cytotoxicity, Immunologic , Immunotherapy , Neoplasms , T-Lymphocytes, Regulatory , Animals , Female , Humans , Male , Mice , Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Chemokine CCL5/metabolism , Dendritic Cells/immunology , Granzymes/metabolism , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Interleukin-10/metabolism , Interleukin-10/immunology , Mice, Inbred C57BL , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes, Regulatory/immunology , Receptors, Immunologic/antagonists & inhibitors , Membrane Glycoproteins/antagonists & inhibitors , Immune Tolerance , CD8-Positive T-Lymphocytes/immunologyABSTRACT
Extracellular deposition of amyloid-ß as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer's disease1,2. The regional progression of brain atrophy in Alzheimer's disease highly correlates with tau accumulation but not amyloid deposition3-5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-ß or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer's disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer's disease and primary tauopathies.