ABSTRACT
Mucosal-associated invariant T (MAIT) cells have been attracting increasing attention over the last few years as a potent unconventional T cell subset. Three factors largely account for this emerging interest. Firstly, these cells are abundant in humans, both in circulation and especially in some tissues such as the liver. Secondly is the discovery of a ligand that has uncovered their microbial targets, and also allowed for the development of tools to accurately track the cells in both humans and mice. Finally, it appears that the cells not only have a diverse range of functions but also are sensitive to a range of inflammatory triggers that can enhance or even bypass T cell receptor-mediated signals-substantially broadening their likely impact in health and disease. In this review we discuss how MAIT cells display antimicrobial, homeostatic, and amplifier roles in vivo, and how this may lead to protection and potentially pathology.
Subject(s)
Disease Susceptibility , Homeostasis , Mucosal-Associated Invariant T Cells/immunology , Mucosal-Associated Invariant T Cells/metabolism , Animals , Biomarkers , Host-Pathogen Interactions , Humans , Immunity, Mucosal , Mucous Membrane/immunology , Mucous Membrane/metabolism , Mucous Membrane/microbiology , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
The immune system is responsible for defending an organism against the myriad of microbial invaders it constantly confronts. It has become increasingly clear that the immune system has a second major function: the maintenance of organismal homeostasis. Foxp3(+)CD4(+) regulatory T cells (Tregs) are important contributors to both of these critical activities, defense being the primary purview of Tregs circulating through lymphoid organs, and homeostasis ensured mainly by their counterparts residing in parenchymal tissues. This review focuses on so-called tissue Tregs. We first survey existing information on the phenotype, function, sustaining factors, and human equivalents of the three best-characterized tissue-Treg populations-those operating in visceral adipose tissue, skeletal muscle, and the colonic lamina propria. We then attempt to distill general principles from this body of work-as concerns the provenance, local adaptation, molecular sustenance, and targets of action of tissue Tregs, in particular.
Subject(s)
Adipose Tissue/immunology , Colon/immunology , Mucous Membrane/immunology , Muscle, Skeletal/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Forkhead Transcription Factors/metabolism , Homeostasis , Humans , Organ SpecificityABSTRACT
Over the past 15 years, investigators have shown that T lymphocytes can recognize not only peptides in the context of MHC class I and class II molecules but also foreign and self-lipids in association with the nonclassical MHC class I-like molecules, CD1 proteins. In this review, we describe the most recent events in the field, with particular emphasis on (a) structural and functional aspects of lipid presentation by CD1 molecules, (b) the development of CD1d-restricted invariant natural killer T (iNKT) cells and transcription factors required for their differentiation, (c) the ability of iNKT cells to modulate innate and adaptive immune responses through their cross talk with lymphoid and myeloid cells, and (d) MR1-restricted and group I (CD1a, CD1b, and CD1c)-restricted T cells.
Subject(s)
Antigens, CD1/immunology , Histocompatibility Antigens Class I/immunology , Natural Killer T-Cells/immunology , Animals , Antigens, CD1/metabolism , Cell Differentiation , Histocompatibility Antigens Class I/metabolism , Humans , Ligands , Lymphocyte Activation/immunology , Minor Histocompatibility Antigens , Mucous Membrane/cytology , Mucous Membrane/immunology , Mucous Membrane/metabolism , Natural Killer T-Cells/cytology , Natural Killer T-Cells/metabolism , Peyer's Patches/cytology , Peyer's Patches/immunology , Peyer's Patches/metabolism , Protein Binding/immunology , Receptors, Antigen, T-Cell/metabolism , T-Cell Antigen Receptor Specificity/immunologyABSTRACT
Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells. In homeostatic Th17 cells, partial blockade of glycolysis upon Gpi1 inactivation was compensated by pentose phosphate pathway flux and increased mitochondrial respiration. In contrast, inflammatory Th17 cells experience a hypoxic microenvironment known to limit mitochondrial respiration, which is incompatible with loss of Gpi1. Our study suggests that inhibiting glycolysis by targeting Gpi1 could be an effective therapeutic strategy with minimum toxicity for Th17-mediated autoimmune diseases, and, more generally, that metabolic redundancies can be exploited for selective targeting of disease processes.
Subject(s)
Cell Differentiation/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Glucose-6-Phosphate Isomerase/metabolism , Glycolysis/genetics , Oxidative Phosphorylation , Pentose Phosphate Pathway/physiology , Th17 Cells/metabolism , Animals , Cell Hypoxia/genetics , Cell Hypoxia/immunology , Chimera/genetics , Chromatography, Gas , Chromatography, Liquid , Clostridium Infections/immunology , Cytokines/deficiency , Cytokines/genetics , Cytokines/metabolism , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Glucose-6-Phosphate Isomerase/genetics , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics , Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/metabolism , Glycolysis/immunology , Homeostasis/genetics , Homeostasis/immunology , Inflammation/genetics , Inflammation/immunology , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Mucous Membrane/immunology , Mucous Membrane/metabolism , Mucous Membrane/microbiology , Pentose Phosphate Pathway/genetics , Pentose Phosphate Pathway/immunology , RNA-Seq , Single-Cell Analysis , Th17 Cells/immunology , Th17 Cells/pathologyABSTRACT
Mucosal surfaces are colonized by large communities of commensal bacteria and represent the primary site of entry for pathogenic agents. To prevent microbial intrusion, mucosal B cells release large amounts of immunoglobulin (Ig) molecules through multiple follicular and extrafollicular pathways. IgA is the most abundant antibody isotype in mucosal secretions and owes its success in frontline immunity to its ability to undergo transcytosis across epithelial cells. In addition to translocating IgA onto the mucosal surface, epithelial cells educate the mucosal immune system as to the composition of the local microbiota and instruct B cells to initiate IgA responses that generate immune protection while preserving immune homeostasis. Here we review recent advances in our understanding of the cellular interactions and signaling pathways governing IgA production at mucosal surfaces and discuss new findings on the regulation and function of mucosal IgD, the most enigmatic isotype of our mucosal antibody repertoire.
Subject(s)
Immunity, Mucosal , Immunoglobulin A/immunology , Mucous Membrane/immunology , Animals , B-Lymphocytes/immunology , Humans , Immunoglobulin D/immunology , Mucous Membrane/microbiology , T-Lymphocytes/immunologyABSTRACT
Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (TH2)-skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b+OX40L+ dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate TH2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.
Subject(s)
Cystitis/etiology , Cystitis/metabolism , Lymphocyte Activation/immunology , Mucous Membrane/immunology , Mucous Membrane/metabolism , Th2 Cells/immunology , Th2 Cells/metabolism , Animals , Bacterial Load , Biomarkers , Cell Line , Cystitis/pathology , Cytokines/metabolism , Disease Models, Animal , Female , Mice , Mice, Knockout , Mucous Membrane/pathology , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/pathology , Urinary Tract Infections/etiology , Urinary Tract Infections/metabolism , Urinary Tract Infections/microbiology , Wound Healing/genetics , Wound Healing/immunologyABSTRACT
An emerging family of innate lymphoid cells (termed ILCs) has an essential role in the initiation and regulation of inflammation. However, it is still unclear how ILCs are regulated in the duration of intestinal inflammation. Here, we identify a regulatory subpopulation of ILCs (called ILCregs) that exists in the gut and harbors a unique gene identity that is distinct from that of ILCs or regulatory T cells (Tregs). During inflammatory stimulation, ILCregs can be induced in the intestine and suppress the activation of ILC1s and ILC3s via secretion of IL-10, leading to protection against innate intestinal inflammation. Moreover, TGF-ß1 is induced by ILCregs during the innate intestinal inflammation, and autocrine TGF-ß1 sustains the maintenance and expansion of ILCregs. Therefore, ILCregs play an inhibitory role in the innate immune response, favoring the resolution of intestinal inflammation.
Subject(s)
Colitis/immunology , Immunity, Innate , Lymphocytes/cytology , Lymphocytes/immunology , Mucous Membrane/cytology , Mucous Membrane/immunology , Animals , B-Lymphocytes/immunology , Homeodomain Proteins/genetics , Homeodomain Proteins/immunology , Humans , Interleukin-10/genetics , Interleukin-10/immunology , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Specific Pathogen-Free Organisms , T-Lymphocytes, Regulatory/immunology , Transforming Growth Factor beta1/immunologyABSTRACT
Multidirectional interactions between the nervous and immune systems have been documented in homeostasis and pathologies ranging from multiple sclerosis to autism, and from leukemia to acute and chronic inflammation. Recent studies have addressed this crosstalk using cell-specific targeting, novel sequencing, imaging, and analytical tools, shedding light on unappreciated mechanisms of neuro-immune regulation. This Review focuses on neuro-immune interactions at barrier surfaces-mostly the gut, but also including the skin and the airways, areas densely populated by neurons and immune cells that constantly sense and adapt to tissue-specific environmental challenges.
Subject(s)
Immune System/metabolism , Mucous Membrane/immunology , Mucous Membrane/innervation , Nervous System/anatomy & histology , Animals , Hematopoiesis , Humans , Intestinal Mucosa/immunology , Intestinal Mucosa/innervation , Intestines/immunology , Intestines/innervation , Lymphoid Tissue/immunology , Lymphoid Tissue/physiology , Nervous System/metabolism , Neurons/cytologyABSTRACT
CD8+ T cell immunosurveillance dynamics influence the outcome of intracellular infections and cancer. Here we used two-photon intravital microscopy to visualize the responses of CD8+ resident memory T cells (TRM cells) within the reproductive tracts of live female mice. We found that mucosal TRM cells were highly motile, but paused and underwent in situ division after local antigen challenge. TRM cell reactivation triggered the recruitment of recirculating memory T cells that underwent antigen-independent TRM cell differentiation in situ. However, the proliferation of pre-existing TRM cells dominated the local mucosal recall response and contributed most substantially to the boosted secondary TRM cell population. We observed similar results in skin. Thus, TRM cells can autonomously regulate the expansion of local immunosurveillance independently of central memory or proliferation in lymphoid tissue.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunity, Mucosal/immunology , Immunologic Memory/immunology , Immunologic Surveillance/immunology , Mucous Membrane/immunology , Animals , Female , Intravital Microscopy , Mice , Mucous Membrane/cytology , Skin/immunologyABSTRACT
People living with HIV (PLWH) are at increased risk for developing skin and mucosal malignancies despite systemic reconstitution of CD4+ T cells upon antiretroviral therapy (ART). The underlying mechanism of chronic tissue-related immunodeficiency in HIV is unclear. We found that skin CD4+ tissue-resident memory T (Trm) cells were depleted after HIV infection and replenished only upon early ART initiation. TCR clonal analysis following early ART suggested a systemic origin for reconstituting CD4+ Trm cells. Single-cell RNA sequencing in PLWH that received late ART treatment revealed a loss of CXCR3+ Trm cells and a tolerogenic skin immune environment. Human papilloma virus-induced precancerous lesion biopsies showed reduced CXCR3+ Trm cell frequencies in the mucosa in PLWH versus HIV- individuals. These results reveal an irreversible loss of CXCR3+ Trm cells confined to skin and mucosa in PLWH who received late ART treatment, which may be a precipitating factor in the development of HPV-related cancer.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV-1/physiology , Immunologic Deficiency Syndromes/immunology , Memory T Cells/immunology , Mucous Membrane/immunology , Skin/immunology , Adult , Antiretroviral Therapy, Highly Active , Female , HIV Infections/drug therapy , HIV Long-Term Survivors , Humans , Immunologic Deficiency Syndromes/drug therapy , Male , Middle Aged , Receptors, CXCR3/metabolism , Sequence Analysis, RNA , Single-Cell Analysis , Time-to-Treatment , Young AdultABSTRACT
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (Treg) cell development and function have been identified3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive Treg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector Treg (eTreg) cell function. eTreg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103+SIRPα+ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206+ macrophages and eTreg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
Subject(s)
Intestinal Mucosa , Mucous Membrane , T-Lymphocytes, Regulatory , Animals , Female , Male , Mice , Antigens, CD/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Gene Expression Profiling , Helicobacter hepaticus/immunology , Helicobacter Infections/immunology , Helicobacter Infections/microbiology , Immune Tolerance/immunology , Inflammation/immunology , Inflammation/microbiology , Inflammation/pathology , Integrin alpha Chains/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , Macrophages/immunology , Macrophages/metabolism , Mice, Inbred C57BL , Mucous Membrane/cytology , Mucous Membrane/immunology , Receptors, Immunologic/metabolism , Receptors, Immunologic/immunology , Single-Cell Gene Expression Analysis , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/cytology , TranscriptomeABSTRACT
Mechanisms for human memory T cell differentiation and maintenance have largely been inferred from studies of peripheral blood, though the majority of T cells are found in lymphoid and mucosal sites. We present here a multidimensional, quantitative analysis of human T cell compartmentalization and maintenance over six decades of life in blood, lymphoid, and mucosal tissues obtained from 56 individual organ donors. Our results reveal that the distribution and tissue residence of naive, central, and effector memory, and terminal effector subsets is contingent on both their differentiation state and tissue localization. Moreover, T cell homeostasis driven by cytokine or TCR-mediated signals is different in CD4+ or CD8+ T cell lineages, varies with their differentiation stage and tissue localization, and cannot be inferred from blood. Our data provide an unprecedented spatial and temporal map of human T cell compartmentalization and maintenance, supporting distinct pathways for human T cell fate determination and homeostasis.
Subject(s)
Aging/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Adolescent , Adult , Aged , CD28 Antigens/metabolism , Cell Differentiation , Child , Child, Preschool , Humans , Interleukin-7 Receptor alpha Subunit/metabolism , Lymphoid Tissue/cytology , Lymphoid Tissue/immunology , Middle Aged , Mucous Membrane/cytology , Mucous Membrane/immunology , Receptors, Antigen, T-Cell/chemistry , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes/metabolism , Tissue Donors , Young AdultABSTRACT
Mucosal surfaces are exposed to environmental substances and represent a major portal of entry for microorganisms. The innate immune system is responsible for early defense against infections and it is believed that the interferons (IFNs) constitute the first line of defense against viruses. Here we identify an innate antiviral pathway that works at epithelial surfaces before the IFNs. The pathway is activated independently of known innate sensors of viral infections through a mechanism dependent on viral O-linked glycans, which induce CXCR3 chemokines and stimulate antiviral activity in a manner dependent on neutrophils. This study therefore identifies a previously unknown layer of antiviral defense that exerts its action on epithelial surfaces before the classical IFN response is operative.
Subject(s)
Immunity, Innate , Interferons/metabolism , Mucous Membrane/immunology , Mucous Membrane/metabolism , Virus Diseases/immunology , Virus Diseases/metabolism , Animals , Cell Line , Chemokine CXCL10/biosynthesis , Disease Models, Animal , Female , Gene Expression , Glycosylation , Herpes Simplex/genetics , Herpes Simplex/immunology , Herpes Simplex/metabolism , Herpes Simplex/virology , Herpesvirus 2, Human/immunology , Humans , Interferons/genetics , Ligands , Mice , Mice, Knockout , Mucous Membrane/virology , Neutrophils/immunology , Neutrophils/metabolism , Polysaccharides/immunology , Receptors, CXCR3/deficiency , Receptors, CXCR3/metabolism , Vagina/immunology , Vagina/metabolism , Vagina/virology , Viral Envelope Proteins/immunology , Viral Envelope Proteins/metabolism , Viral Load , Virus Diseases/virologyABSTRACT
The epithelial lining of the respiratory tract and intestine provides a critical physical barrier to protect host tissues against environmental insults, including dietary antigens, allergens, chemicals, and microorganisms. In addition, specialized epithelial cells communicate directly with hematopoietic and neuronal cells. These epithelial-immune and epithelial-neuronal interactions control host immune responses and have important implications for inflammatory conditions associated with defects in the epithelial barrier, including asthma, allergy, and inflammatory bowel diseases. In this review, we discuss emerging research that identifies the mechanisms and impact of epithelial-immune and epithelial-neuronal cross talk in regulating immunity, inflammation, and tissue homeostasis at mucosal barrier surfaces. Understanding the regulation and impact of these pathways could provide new therapeutic targets for inflammatory diseases at mucosal sites.
Subject(s)
Epithelial Cells , Homeostasis , Inflammation , Neurons , Humans , Homeostasis/immunology , Animals , Inflammation/immunology , Epithelial Cells/immunology , Neurons/immunology , Cell Communication/immunology , Immunity, Mucosal , Intestinal Mucosa/immunology , Mucous Membrane/immunologyABSTRACT
BACKGROUND: Inborn errors of immunity offer important insights into mucosal immunity. In autoimmune polyendocrine syndrome type-1 (APS-1), chronic mucocutaneous candidiasis has been ascribed to neutralizing IL-17 autoantibodies. Recent evidence implicates excessive T-cell IFN-γ secretion and ensuing epithelial barrier disruption in predisposition to candidiasis, but these results remain to be replicated. Whether IL-17 paucity, increased type I inflammation, or their combination underlies susceptibility to chronic mucocutaneus candidiasis in APS-1 is debated. OBJECTIVE: Our aim was to characterize the immunologic features in the cervicovaginal mucosa of females with APS-1. METHODS: Vaginal fluid was collected with a flocked swab from 17 females with APS-1 and 18 controls, and cytokine composition was analyzed using Luminex (Luminex Corporation, Austin, Tex). Cervical cell samples were obtained with a cervix brush from 6 patients and 6 healthy controls and subjected to transcriptome analysis. RESULTS: The vaginal fluid samples from patients with APS-1 had IFN-γ concentrations comparable to those of the controls (2.6 vs 2.4 pg/mL) but high concentrations of the TH1 chemokines CXCL9 and CXCL10 (1094 vs 110 pg/mL [P < .001] and 4033 vs 273 pg/mL [P = .001], respectively), whereas the IL-17 levels in the samples from the 2 groups were comparable (28 vs 8.8 pg/mL). RNA sequencing of the cervical cells revealed upregulation of pathways related to mucosal inflammation and cell death in the patients with APS-1. CONCLUSION: Excessive TH1 cell response appears to underlie disruption of the mucosal immune responses in the genital tract of patients with APS-1 and may contribute to susceptibility to candidiasis in the genital tract as well.
Subject(s)
Cervix Uteri , Polyendocrinopathies, Autoimmune , Vagina , Humans , Female , Vagina/immunology , Polyendocrinopathies, Autoimmune/immunology , Adult , Cervix Uteri/immunology , Cervix Uteri/pathology , Middle Aged , Cytokines/metabolism , Cytokines/immunology , Inflammation/immunology , Interleukin-17/immunology , Interleukin-17/metabolism , Chemokine CXCL9/immunology , Chemokine CXCL9/metabolism , Young Adult , Interferon-gamma/immunology , Interferon-gamma/metabolism , Candidiasis, Chronic Mucocutaneous/immunology , Candidiasis, Chronic Mucocutaneous/genetics , Mucous Membrane/immunologyABSTRACT
Type-2-cell-mediated immunity, rich in eosinophils, basophils, mast cells, CD4(+) T helper 2 (Th2) cells, and type 2 innate lymphoid cells (ILC2s), protects the host from helminth infection but also drives chronic allergic diseases like asthma and atopic dermatitis. Barrier epithelial cells (ECs) represent the very first line of defense and express pattern recognition receptors to recognize type-2-cell-mediated immune insults like proteolytic allergens or helminths. These ECs mount a prototypical response made up of chemokines, innate cytokines such as interleukin-1 (IL-1), IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), as well as the alarmins uric acid, ATP, HMGB1, and S100 proteins. These signals program dendritic cells (DCs) to mount Th2-cell-mediated immunity and in so doing boost ILC2, basophil, and mast cell function. Here we review the general mechanisms of how different stimuli trigger type-2-cell-mediated immunity at mucosal barriers and how this leads to protection or disease.
Subject(s)
Epithelial Cells/immunology , Helminthiasis/immunology , Hypersensitivity/immunology , Immunity, Cellular/immunology , Mucous Membrane/immunology , Animals , Chemokines/immunology , Cytokines/immunology , Dendritic Cells/immunology , Humans , Mucous Membrane/parasitology , Th2 Cells/immunology , Tight Junctions/immunologyABSTRACT
Colonization with a mixture of Clostridium species has been shown to induce accumulation of induced regulatory T (iTreg) cells in the colon. Transforming growth factor-ß (TGF-ß) is an essential factor for iTreg cell induction; however, the relationship between Clostridium species and TGF-ß remains to be clarified. Here we demonstrated that a gram-positive probiotic bacterial strain, Clostridium butyricum (C. butyricum), promoted iTreg cell generation in the intestine through induction of TGF-ß1 from lamina propria dendritic cells (LPDCs). C. butyricum-mediated TGF-ß1 induction was mainly Toll-like receptor 2 (TLR2) dependent, and the ERK-AP-1 kinase pathway played an important role. In addition, the autocrine TGF-ß-Smad3 transcription factor signal was necessary for robust TGF-ß expression in DCs, whereas Smad2 negatively regulated TGF-ß expression. Smad2-deficient DCs expressed higher concentrations of TGF-ß and were tolerogenic for colitis models. This study reveals a novel mechanism of TGF-ß induction by Clostridia through a cooperation between TLR2-AP-1 and TGF-ß-Smad signaling pathways.
Subject(s)
Clostridium butyricum/immunology , Dendritic Cells/immunology , Smad2 Protein/genetics , Smad3 Protein/genetics , Transforming Growth Factor beta1/biosynthesis , Animals , Clostridium Infections/immunology , Clostridium Infections/microbiology , Colitis/immunology , Extracellular Signal-Regulated MAP Kinases/immunology , Intestines/immunology , Intestines/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mucous Membrane/cytology , Mucous Membrane/immunology , Promoter Regions, Genetic/genetics , T-Lymphocytes, Regulatory/immunology , Toll-Like Receptor 2/immunology , Transcription Factor AP-1/immunology , Transforming Growth Factor beta1/geneticsABSTRACT
Many vaccine candidates with promising results in preclinical testing fail in human trials. New complex human tissue models have the potential to improve the predictability of vaccine safety and efficacy in human clinical trials.
Subject(s)
Drug Evaluation, Preclinical , Models, Biological , Mucous Membrane/immunology , Vaccines/immunology , Bioreactors , Host-Pathogen Interactions/immunology , Humans , Immunity , PerfusionABSTRACT
The study was designed to investigate the effects of replacing fish oil by algal oil and rapeseed oil on histomorphology indices of the intestine, skin and gill, mucosal barrier status and immune-related genes of mucin and antimicrobial peptide (AMP) genes in Atlantic salmon (Salmo salar). For these purposes, Atlantic salmon smolts were fed three different diets. The first was a control diet containing fish oil but no Schizochytrium oil. In the second diet, almost 50 % of the fish oil was replaced with algal oil, and in the third diet, fish oil was replaced entirely with algal oil. The algal oil contained mostly docosahexaenoic acid (DHA) and some eicosapentaenoic acid (EPA). The study lasted for 49 days in freshwater (FW), after which some fish from each diet group were transferred to seawater (SW) for a 48-h challenge test at 33 ppt to test their ability to tolerate high salinity. Samples of skin, gills, and mid intestine [both distal (DI) and anterior (AI) portions of the mid intestine] were collected after the feeding trial in FW and after the SW-challenge test to assess the effects of the diets on the structure and immune functions of the mucosal surfaces. The results showed that the 50 % VMO (Veramaris® algal oil) dietary group had improved intestinal, skin, and gill structures. Principal component analysis (PCA) of the histomorphological parameters demonstrated a significant effect of the algal oil on the intestine, skin, and gills. In particular, the mucosal barrier function of the intestine, skin, and gills was enhanced in the VMO 50 % dietary group after the SW challenge, as evidenced by increased mucous cell density. Immunolabelling of heat shock protein 70 (HSP70) in the intestine (both DI and AI) revealed downregulation of the protein expression in the 50 % VMO group and a corresponding upregulation in the 100 % VMO group compared to 0 % VMO. The reactivity of HSP70 in the epithelial cells was higher after the SW challenge compared to the FW phase. Immune-related genes related to mucosal defense, such as mucin genes [muc2, muc5ac1 (DI), muc5ac1 (AI), muc5ac2, muc5b (skin), and muc5ac1 (gills)], and antimicrobial peptide genes [def3 (DI), def3 (AI), and cath1 (skin)] were significantly upregulated in the 50 % VMO group. PCA of gene expression demonstrated the positive influences on gene regulation in the 50 % VMO dietary group. In conclusion, this study demonstrated the positive effect of substituting 50 % of fish oil with algal oil in the diets of Atlantic salmon. The findings of histomorphometry, mucosal mapping, immunohistochemistry, and immune-related genes connected to mucosal responses all support this conclusion.
Subject(s)
Animal Feed , Diet , Rapeseed Oil , Salmo salar , Animals , Salmo salar/immunology , Diet/veterinary , Rapeseed Oil/chemistry , Animal Feed/analysis , Mucous Membrane/immunology , Fish Oils/administration & dosage , Skin/immunology , Skin/drug effects , Seasons , Gills/immunology , Gills/drug effects , Intestines/drug effects , Intestines/immunologyABSTRACT
The gastrointestinal tract of mammals is inhabited by hundreds of distinct species of commensal microorganisms that exist in a mutualistic relationship with the host. How commensal microbiota influence the host immune system is poorly understood. We show here that colonization of the small intestine of mice with a single commensal microbe, segmented filamentous bacterium (SFB), is sufficient to induce the appearance of CD4(+) T helper cells that produce IL-17 and IL-22 (Th17 cells) in the lamina propria. SFB adhere tightly to the surface of epithelial cells in the terminal ileum of mice with Th17 cells but are absent from mice that have few Th17 cells. Colonization with SFB was correlated with increased expression of genes associated with inflammation and antimicrobial defenses and resulted in enhanced resistance to the intestinal pathogen Citrobacter rodentium. Thus, manipulation of this commensal-regulated pathway may provide new opportunities for enhancing mucosal immunity and treating autoimmune disease.