ABSTRACT
The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer.
Subject(s)
Intestinal Mucosa , Intraepithelial Lymphocytes , Humans , Animals , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Homeostasis , Receptors, Antigen, T-Cell/metabolism , Intestines/immunologyABSTRACT
Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.
Subject(s)
Cytokines , Wounds and Injuries , Animals , Mice , Adaptive Immunity , Chemokines , Epidermis , Immunity, Innate , Wounds and Injuries/immunologyABSTRACT
How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection. Microbiota-induced Th17 cells afforded protection by regulating lipid absorption across intestinal epithelium in an IL-17-dependent manner. Diet-induced loss of protective Th17 cells was mediated by the presence of sugar. Eliminating sugar from high-fat diets protected mice from obesity and metabolic syndrome in a manner dependent on commensal-specific Th17 cells. Sugar and ILC3 promoted outgrowth of Faecalibaculum rodentium that displaced Th17-inducing microbiota. These results define dietary and microbiota factors posing risk for metabolic syndrome. They also define a microbiota-dependent mechanism for immuno-pathogenicity of dietary sugar and highlight an elaborate interaction between diet, microbiota, and intestinal immunity in regulation of metabolic disorders.
Subject(s)
Metabolic Syndrome , Microbiota , Animals , Diet, High-Fat , Dietary Sugars , Interleukin-17 , Intestinal Mucosa , Lipids , Mice , Mice, Inbred C57BL , Obesity , Th17 CellsABSTRACT
Regulatory T lymphocytes are essential to maintain homeostasis of the immune system, limiting the magnitude of effector responses and allowing the establishment of immunological tolerance. Two main types of regulatory T cells have been identified--natural and induced (or adaptive)-and both play significant roles in tuning down effector immune responses. Adaptive CD4(+)Foxp3(+) regulatory T (iTreg) cells develop outside the thymus under a variety of conditions. These include not only antigen presentation under subimmunogenic or noninflammatory conditions, but also chronic inflammation and infections. We speculate that the different origin of iTreg cells (noninflammatory versus inflammatory) results in distinct properties, including their stability. iTreg cells are also generated during homeostasis of the gut and in cancer, although some cancers also favor expansion of natural regulatory T (nTreg) cells. Here we review how iTreg cells develop and how they participate in immunological tolerance, contrasting, when possible, iTreg cells with nTreg cells.
Subject(s)
Immune Tolerance/immunology , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , CD4 Antigens/metabolism , Forkhead Transcription Factors/metabolism , Humans , Lymphoid Tissue/immunology , Lymphoid Tissue/metabolism , T-Lymphocytes, Regulatory/metabolismABSTRACT
Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinal lamina propria and epithelium, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we uncovered the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (Treg) CD4+ T cells from mLN, lamina propria and intestinal epithelium segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4 programming and acquisition of an intraepithelial profile. Treg cell fate mapping coupled with RNA sequencing and assay for transposase-accessible chromatin followed by sequencing revealed that the Treg cell program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of CD4-lineage-defining transcription factor ThPOK results in premature acquisition of an intraepithelial lymphocyte profile by mLN Treg cells, partially recapitulating epithelium imprinting. Thus, coordinated replacement of the circulating lymphocyte program with site-specific transcriptional and chromatin changes is necessary for tissue imprinting.
Subject(s)
Cell Differentiation , Chromatin Assembly and Disassembly , Genomic Imprinting , Intestinal Mucosa/metabolism , Intraepithelial Lymphocytes/metabolism , Lymph Nodes/metabolism , T-Lymphocytes, Regulatory/metabolism , Transcription, Genetic , Animals , Cell Lineage , Cells, Cultured , Gene Expression Profiling , Gene Expression Regulation, Developmental , Intestinal Mucosa/immunology , Intraepithelial Lymphocytes/immunology , Lymph Nodes/immunology , Mice, Knockout , Phenotype , RNA-Seq , Single-Cell Analysis , T-Lymphocytes, Regulatory/immunology , Transcription Factors/genetics , Transcription Factors/metabolism , TranscriptomeABSTRACT
Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function1. To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts)2, an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4+ T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8+ T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8+ T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems.
Subject(s)
B-Lymphocytes , CD8-Positive T-Lymphocytes , Cell Communication , Dendritic Cells , Epithelial Cells , T Follicular Helper Cells , T-Lymphocytes, Regulatory , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cell Communication/immunology , Dendritic Cells/cytology , Dendritic Cells/immunology , Ligands , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/immunology , T Follicular Helper Cells/cytology , T Follicular Helper Cells/immunology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , Germinal Center/cytology , Single-Cell Gene Expression Analysis , Epithelial Cells/cytology , Epithelial Cells/immunology , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , Lymphocytic choriomeningitis virus/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Organ SpecificityABSTRACT
The gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties, which can be acquired at the epithelial layer. However, the role of T cell receptor (TCR) in this process remains unclear. Single-cell transcriptomic analyses revealed distinct clonal expansions between cell states, with CD4+CD8αα+ IELs being one of the least diverse populations. Conditional deletion of TCR on differentiating CD4+ T cells or of major histocompatibility complex (MHC) class II on intestinal epithelial cells prevented CD4+CD8αα+ IEL differentiation. However, TCR ablation on differentiated CD4+CD8αα+ IELs or long-term cognate antigen withdraw did not affect their maintenance. TCR re-engagement of antigen-specific CD4+CD8αα+ IELs by Listeria monocytogenes did not alter their state but correlated with reduced bacterial invasion. Thus, local antigen recognition is an essential signal for differentiation of CD4+ T cells at the epithelium, yet differentiated IELs are able to preserve an effector program in the absence of TCR signaling.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Receptors, Antigen, T-Cell/metabolism , Animals , Cell Differentiation/genetics , Cell Differentiation/immunology , Clonal Evolution/genetics , Clonal Evolution/immunology , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Immunophenotyping , Mice , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Signal Transduction , Single-Cell Analysis , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismABSTRACT
Germinal centres, the structures in which B cells evolve to produce antibodies with high affinity for various antigens, usually form transiently in lymphoid organs in response to infection or immunization. In lymphoid organs associated with the gut, however, germinal centres are chronically present. These gut-associated germinal centres can support targeted antibody responses to gut infections and immunization1. But whether B cell selection and antibody affinity maturation take place in the face of the chronic and diverse antigenic stimulation characteristic of these structures under steady state is less clear2-8. Here, by combining multicolour 'Brainbow' cell-fate mapping and sequencing of immunoglobulin genes from single cells, we find that 5-10% of gut-associated germinal centres from specific-pathogen-free (SPF) mice contain highly dominant 'winner' B cell clones at steady state, despite rapid turnover of germinal-centre B cells. Monoclonal antibodies derived from these clones show increased binding, compared with their unmutated precursors, to commensal bacteria, consistent with antigen-driven selection. The frequency of highly selected gut-associated germinal centres is markedly higher in germ-free than in SPF mice, and winner B cells in germ-free germinal centres are enriched in 'public' clonotypes found in multiple individuals, indicating strong selection of B cell antigen receptors even in the absence of microbiota. Colonization of germ-free mice with a defined microbial consortium (Oligo-MM12) does not eliminate germ-free-associated clonotypes, yet does induce a concomitant commensal-specific B cell response with the hallmarks of antigen-driven selection. Thus, positive selection of B cells can take place in steady-state gut-associated germinal centres, at a rate that is tunable over a wide range by the presence and composition of the microbiota.
Subject(s)
B-Lymphocytes/immunology , Clonal Selection, Antigen-Mediated , Gastrointestinal Microbiome/immunology , Germinal Center/cytology , Germinal Center/immunology , Intestines/immunology , Intestines/microbiology , Amino Acid Sequence , Animals , B-Lymphocytes/cytology , Clone Cells/cytology , Clone Cells/immunology , Female , Germ-Free Life , Intestines/cytology , Kinetics , Male , MiceABSTRACT
Current therapies for autoimmune diseases rely on traditional immunosuppressive medications that expose patients to an increased risk of opportunistic infections and other complications. Immunoregulatory interventions that act prophylactically or therapeutically to induce antigen-specific tolerance might overcome these obstacles. Here we use the transpeptidase sortase to covalently attach disease-associated autoantigens to genetically engineered and to unmodified red blood cells as a means of inducing antigen-specific tolerance. This approach blunts the contribution to immunity of major subsets of immune effector cells (B cells, CD4+ and CD8+ T cells) in an antigen-specific manner. Transfusion of red blood cells expressing self-antigen epitopes can alleviate and even prevent signs of disease in experimental autoimmune encephalomyelitis, as well as maintain normoglycemia in a mouse model of type 1 diabetes.
ABSTRACT
mAbs specific for surface proteins on APCs can serve as Ag-delivery vehicles that enhance immunogenicity. The practical use of such constructs is limited by the challenge of expressing and modifying full-sized mAbs. We generated single-domain Ab fragments (VHHs) specific for class II MHC (MHCII), CD11b, and CD36. VHH sequences were modified by inclusion of a C-terminal sortase motif to allow site-specific conjugation with various Ag payloads. We tested T cell activation using VHHs that target distinct APC populations; anti-MHCII adducts elicited strong activation of CD4+ T cells, whereas anti-CD11b showed CD8+ T cell activation superior to targeting via MHCII and CD36. Differences in Ag presentation among constructs were unrelated to dendritic cell subtype or routing to acidic compartments. When coupled to antigenic payloads, anti-MHCII VHH primed Ab responses against GFP, ubiquitin, an OVA peptide, and the α-helix of influenza hemagglutinin's stem; the last afforded protection against influenza infection. The versatility of the VHH scaffold and sortase-mediated covalent attachment of Ags suggests their broader application to generate desirable immune responses.
Subject(s)
Antigen-Antibody Complex/metabolism , Dendritic Cells/physiology , Hemagglutinin Glycoproteins, Influenza Virus/metabolism , Influenza Vaccines/immunology , Influenza, Human/immunology , Orthomyxoviridae Infections/immunology , Single-Domain Antibodies/metabolism , Animals , Antigen Presentation , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Camelids, New World , Cells, Cultured , Histocompatibility Antigens Class II/metabolism , Humans , Influenza, Human/prevention & control , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae Infections/prevention & control , Single-Domain Antibodies/immunologyABSTRACT
At their margins, tumors often contain neutrophils, dendritic cells, and activated macrophages, which express class II MHC and CD11b products. The interplay between stromal cells, tumor cells, and migratory cells such as lymphocytes creates opportunities for noninvasive imaging of immune responses. We developed alpaca-derived antibody fragments specific for mouse class II MHC and CD11b products, expressed on the surface of a variety of myeloid cells. We validated these reagents by flow cytometry and two-photon microscopy to obtain images at cellular resolution. To enable noninvasive imaging of the targeted cell populations, we developed a method to site-specifically label VHHs [the variable domain (VH) of a camelid heavy-chain only antibody] with (18)F or (64)Cu. Radiolabeled VHHs rapidly cleared the circulation (t1/2 ≈ 20 min) and clearly visualized lymphoid organs. We used VHHs to explore the possibility of imaging inflammation in both xenogeneic and syngeneic tumor models, which resulted in detection of tumors with remarkable specificity. We also imaged the infiltration of myeloid cells upon injection of complete Freund's adjuvant. Both anti-class II MHC and anti-CD11b VHHs detected inflammation with excellent specificity. Given the ease of manufacture and labeling of VHHs, we believe that this method could transform the manner in which antitumor responses and/or infectious events may be tracked.
Subject(s)
Immune System/physiology , Neoplasms/immunology , Positron-Emission Tomography , Aminoacyltransferases/physiology , Animals , Antibodies/immunology , Antineoplastic Agents/therapeutic use , Bacterial Proteins/physiology , Bone Marrow Cells/metabolism , Copper Radioisotopes/chemistry , Cysteine Endopeptidases/physiology , Flow Cytometry , Fluorine Radioisotopes/chemistry , Freund's Adjuvant , Histocompatibility Antigens Class II/immunology , Humans , Immunoglobulin Heavy Chains/immunology , Inflammation , Mice , Mice, Inbred C57BL , Myeloid Cells/pathology , Neoplasm Transplantation , Neoplasms/therapyABSTRACT
The site-specific modification of proteins with fluorophores can render a protein fluorescent without compromising its function. To avoid self-quenching from multiple fluorophores installed in close proximity, we used Holliday junctions to label proteins site-specifically. Holliday junctions enable modification with multiple fluorophores at reasonably precise spacing. We designed a Holliday junction with three of its four arms modified with a fluorophore of choice and the remaining arm equipped with a dibenzocyclooctyne substituent to render it reactive with an azide-modified fluorescent single-domain antibody fragment or an intact immunoglobulin produced in a sortase-catalyzed reaction. These fluorescent Holliday junctions improve fluorescence yields for both single-domain and full-sized antibodies without deleterious effects on antigen binding.
Subject(s)
Alkynes/chemistry , Antibodies/analysis , Antibodies/chemistry , Azides/chemistry , DNA, Cruciform/chemistry , Fluorescent Dyes/chemistryABSTRACT
Cellular interactions are essential for tissue organization and functionality. In particular, immune cells rely on direct and usually transient interactions with other immune and non-immune populations to specify and regulate their function. To study these "kiss-and-run" interactions directly in vivo, we previously developed LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts), an approach that uses enzymatic transfer of a labeled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4+ helper T cells and antigen presenting cells, however. Here, we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8+ T cells by dendritic cells, reveal the cellular partners of regulatory T cells in steady state, and identify germinal center (GC)-resident T follicular helper (Tfh) cells based on their ability to interact cognately with GC B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalog of the immune populations that physically interact with intestinal epithelial cells (IECs) and find evidence of stepwise acquisition of the ability to interact with IECs as CD4+ T cells adapt to residence in the intestinal tissue. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems.
ABSTRACT
Thymocytes differentiate into CD4(+) Foxp3(+) regulatory T cells (T(R)) upon interaction between their TCR and peptide-MHC II complexes locally expressed in the thymus. Conversion of naive CD4(+) T cells into T(R) can additionally take place in the periphery under noninflammatory conditions of Ag encounter. In this study, making use of TCR transgenic models naturally devoid of Foxp3(+) cells, we report de novo generation of T(R) upon a single footpad injection of Ag mixed with a classic proinflammatory adjuvant. Abrupt T(R) differentiation upon immunization occurred intrathymically and was essential for robust tolerance induction in a mouse model of spontaneous encephalomyelitis. This phenomenon could be attributed to a specific feature of thymocytes, which, in contrast to mature peripheral CD4(+) T cells, were insensitive to the inhibitory effects of IL-6 on the induction of Foxp3 expression. Our findings uncover a pathway for T(R) generation with major implications for immunity and tolerance induction.
Subject(s)
Cell Differentiation/immunology , Forkhead Transcription Factors/immunology , T-Lymphocyte Subsets/cytology , T-Lymphocytes, Regulatory/cytology , Thymus Gland/cytology , Animals , Encephalomyelitis, Autoimmune, Experimental/immunology , Forkhead Transcription Factors/metabolism , Immune Tolerance/immunology , Immunization , Inflammation/immunology , Interleukin-6/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Thymus Gland/immunologyABSTRACT
γδ T cells represent a substantial fraction of intestinal lymphocytes at homeostasis, but they also constitute a major lymphocyte population infiltrating colorectal cancers (CRCs); however, their temporal contribution to CRC development or progression remains unclear. Using human CRC samples and murine CRC models, we found that most γδ T cells in premalignant or nontumor colons exhibit cytotoxic markers, whereas tumor-infiltrating γδ T cells express a protumorigenic profile. These contrasting T cell profiles were associated with distinct T cell receptor (TCR)-Vγδ gene usage in both humans and mice. Longitudinal intersectional genetics and antibody-dependent strategies targeting murine γδ T cells enriched in the epithelium at steady state led to heightened tumor development, whereas targeting γδ subsets that accumulate during CRC resulted in reduced tumor growth. Our results uncover temporal pro- and antitumor roles for γδ T cell subsets.
Subject(s)
Colorectal Neoplasms , Cytotoxicity, Immunologic , Intestines , Intraepithelial Lymphocytes , Receptors, Antigen, T-Cell, gamma-delta , Animals , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Humans , Intestines/immunology , Intraepithelial Lymphocytes/immunology , Mice , Receptors, Antigen, T-Cell, gamma-delta/genetics , Receptors, Antigen, T-Cell, gamma-delta/physiologyABSTRACT
Efficient mouse models to study SARS-CoV-2 infection are critical for the development and assessment of vaccines and therapeutic approaches to mitigate the current pandemic and prevent reemergence of COVID-19. While the first generation of mouse models allowed SARS-CoV-2 infection and pathogenesis, they relied on ectopic expression and non-physiological levels of human angiotensin-converting enzyme 2 (hACE2). Here we generated a mouse model carrying the minimal set of modifications necessary for productive infection with multiple strains of SARS-CoV-2. Substitution of only three amino acids in the otherwise native mouse Ace2 locus (Ace2 TripleMutant or Ace2™), was sufficient to render mice susceptible to both SARS-CoV-2 strains USA-WA1/2020 and B.1.1.529 (Omicron). Infected Ace2™ mice exhibited weight loss and lung damage and inflammation, similar to COVID-19 patients. Previous exposure to USA-WA1/2020 or mRNA vaccination generated memory B cells that participated in plasmablast responses during breakthrough B.1.1.529 infection. Thus, the Ace2™ mouse replicates human disease after SARS-CoV-2 infection and provides a tool to study immune responses to sequential infections in mice.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Mice , Animals , Angiotensin-Converting Enzyme 2/genetics , Disease Models, Animal , PandemicsABSTRACT
The microbiome contributes to the development and maturation of the immune system. In response to commensal bacteria, intestinal CD4+ T lymphocytes differentiate into functional subtypes with regulatory or effector functions. The development of small intestine intraepithelial lymphocytes that coexpress CD4 and CD8αα homodimers (CD4IELs) depends on the microbiota. However, the identity of the microbial antigens recognized by CD4+ T cells that can differentiate into CD4IELs remains unknown. We identified ß-hexosaminidase, a conserved enzyme across commensals of the Bacteroidetes phylum, as a driver of CD4IEL differentiation. In a mouse model of colitis, ß-hexosaminidase-specific lymphocytes protected against intestinal inflammation. Thus, T cells of a single specificity can recognize a variety of abundant commensals and elicit a regulatory immune response at the intestinal mucosa.
Subject(s)
Bacteroidetes , CD4-Positive T-Lymphocytes , Colitis , Intestinal Mucosa , beta-N-Acetylhexosaminidases , Animals , Bacteroidetes/enzymology , Bacteroidetes/immunology , CD4-Positive T-Lymphocytes/immunology , CD8 Antigens/immunology , Colitis/immunology , Colitis/microbiology , Disease Models, Animal , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Mice , Mice, Inbred C57BL , beta-N-Acetylhexosaminidases/immunologyABSTRACT
Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The formation of GCs has been studied in detail, but less is known about what leads to their regression and eventual termination, factors that ultimately limit the extent to which antibodies mature within a single reaction. We show that contraction of immunization-induced GCs is immediately preceded by an acute surge in GC-resident Foxp3+ T cells, attributed at least partly to up-regulation of the transcription factor Foxp3 by T follicular helper (TFH) cells. Ectopic expression of Foxp3 in TFH cells is sufficient to decrease GC size, implicating the natural up-regulation of Foxp3 by TFH cells as a potential regulator of GC lifetimes.
Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Forkhead Transcription Factors/genetics , Germinal Center/immunology , T Follicular Helper Cells/metabolism , T-Lymphocytes, Regulatory/immunology , Animals , CD4-Positive T-Lymphocytes/physiology , Forkhead Transcription Factors/metabolism , Genes, T-Cell Receptor , Germinal Center/cytology , Immunization , Immunophenotyping , Mice , Mice, Inbred C57BL , Mice, Transgenic , Single-Cell Analysis , T Follicular Helper Cells/immunology , T-Lymphocytes, Regulatory/physiology , Up-RegulationABSTRACT
The pathogenesis of Chagas disease cardiomyopathy (CCC) is not well understood. Since studies show that myocarditis is more frequent during the advanced stages of the disease, and the prognosis of CCC is worse than that of other dilated cardiomyopathies of non-inflammatory aetiology, which suggest that the inflammatory infiltrate plays a major role in myocardial damage. In the last decade, increasing evidence has shown that inflammatory cytokines and chemokines play a role in the generation of the inflammatory infiltrate and tissue damage. CCC patients have an increased peripheral production of the inflammatory Th1 cytokines IFN-gamma and TNF-alpha when compared to patients with the asymptomatic/indeterminate form. Moreover, Th1-T cells are the main producers of IFN-gamma and TNF-alpha and are frequently found in CCC myocardial inflammatory infiltrate. Over the past several years, our group has collected evidence that shows several cytokines and chemokines produced in the CCC myocardium may also have a non-immunological pathogenic effect via modulation of gene and protein expression in cardiomyocytes and other myocardial cell types. Furthermore, genetic polymorphisms of cytokine, chemokine and innate immune response genes have been associated with disease progression. We will review the molecular and immunological mechanisms of myocardial damage in human CCC in light of recent findings.
Subject(s)
Chagas Cardiomyopathy/immunology , Chemokines/immunology , Cytokines/immunology , Acute Disease , Chemokines/genetics , Chronic Disease , Cytokines/genetics , Disease Progression , Humans , Interferon-gamma/genetics , Interferon-gamma/immunology , Polymorphism, Genetic , Th1 Cells/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Chagas disease continues to be a significant public health problem, as ca. 10 million people are still infected with T. cruzi in Latin America. Decades after primary infection, 30% of individuals can develop a form of chronic inflammatory cardiomyopathy known as Chagas disease cardiomyopathy (CCC). Data from both murine models and human studies support the view that an autoimmune response as well as a parasite-driven immune response involving inflammatory cytokines and chemokines may both play a role in generating the heart lesions leading to CCC. This review aims to summarize recent advances in the understanding of the immunopathogenesis of Chagas disease cardiomyopathy.