ABSTRACT
Celiac disease (CD) is a gluten-sensitive enteropathy that develops in genetically susceptible individuals by exposure to cereal gluten proteins. This review integrates insights from immunological studies with results of recent genetic genome-wide association studies into a disease model. Genetic data, among others, suggest that viral infections are implicated and that natural killer effector pathways are important in the pathogenesis of CD, but most prominently these data converge with existing immunological findings that CD is primarily a T cell-mediated immune disorder in which CD4(+) T cells that recognize gluten peptides in the context of major histocompatibility class II molecules play a central role. Comparison of genetic pathways as well as genetic susceptibility loci between CD and other autoimmune and inflammatory disorders reveals that CD bears stronger resemblance to T cell-mediated organ-specific autoimmune than to inflammatory diseases. Finally, we present evidence suggesting that the high prevalence of CD in modern societies may be the by-product of past selection for increased immune responses to combat infections in populations in which agriculture and cereals were introduced early on in the post-Neolithic period.
Subject(s)
Celiac Disease/genetics , Celiac Disease/immunology , Animals , Celiac Disease/epidemiology , Celiac Disease/physiopathology , Genetic Predisposition to Disease , Glutens/immunology , Humans , Risk FactorsABSTRACT
Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies.
Subject(s)
Celiac Disease/immunology , Celiac Disease/pathology , Glutens/immunology , HLA-DQ Antigens/immunology , Interleukin-15/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , Female , HLA-DQ Antigens/genetics , Humans , Interferon-gamma/immunology , Interleukin-15/genetics , Male , Mice , Mice, Transgenic , Microfilament Proteins/genetics , Microfilament Proteins/metabolismABSTRACT
Celiac disease (CeD) is a gluten-induced enteropathy that develops in genetically susceptible individuals upon consumption of cereal gluten proteins. It is a unique and complex immune disorder to study as the driving antigen is known and the tissue targeted by the immune reaction can be interrogated. This review integrates findings gained from genetic, biochemical, and immunologic studies, which together have revealed mechanisms of gluten peptide modification and HLA binding, thereby enabling a maladapted anti-gluten immune response. Observations in human samples combined with experimental mouse models have revealed that the gluten-induced immune response involves CD4+ T cells, cytotoxic CD8+ T cells, and B cells; their cross-talks are critical for the tissue-damaging response. The emergence of high-throughput technologies is increasing our understanding of the phenotype, location, and presumably function of the gluten-specific cells, which are all required to identify novel therapeutic targets and strategies for CeD.
Subject(s)
Celiac Disease , Genetic Predisposition to Disease , Glutens , Celiac Disease/immunology , Celiac Disease/genetics , Humans , Glutens/immunology , Glutens/adverse effects , Animals , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunologyABSTRACT
The bone marrow (BM) has been identified as a possible organ for T cell priming, yet the fundamental mechanisms of a polyclonal immune response in the BM remain unknown. We found that after intradermal injection of modified vaccinia Ankara virus, unexpected sources of newly primed polyclonal virus-specific CD8(+), but not CD4(+), T cells were localized in the BM and the draining lymph nodes (dLNs) prior to blood circulation. We identified neutrophils as the virus-carrier cells from the dermis to the BM. In both neutrophil-depleted and Ccr1(-/-) mice, virus-specific BM CD8(+) responses were lost. Myeloid antigen-presenting cells were required for BM CD8(+) T cell priming. A systems biology analysis of dLN and BM virus-specific CD8(+) T cells revealed distinct transcriptional and multifunctional profiles for cells primed in each organ. We provide direct evidence for how antigen is transported to the BM, providing a source of virus-specific memory CD8(+) T cells.
Subject(s)
Antigens/immunology , Bone Marrow/immunology , CD8-Positive T-Lymphocytes/immunology , Dermis/immunology , Immunologic Memory/immunology , Neutrophils/immunology , Animals , Antigen-Presenting Cells/immunology , CD4-Positive T-Lymphocytes/immunology , Female , Lymph Nodes/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Myeloid Cells/immunology , Receptors, CCR1/immunologyABSTRACT
Interleukin-15 (IL-15) exerts many biological functions essential for the maintenance and function of multiple cell types. Although its expression is tightly regulated, IL-15 upregulation has been reported in many organ-specific autoimmune disorders. In celiac disease, an intestinal inflammatory disorder driven by gluten exposure, the upregulation of IL-15 expression in the intestinal mucosa has become a hallmark of the disease. Interestingly, because it is overexpressed both in the gut epithelium and in the lamina propria, IL-15 acts on distinct cell types and impacts distinct immune components and pathways to disrupt intestinal immune homeostasis. In this article, we review our current knowledge of the multifaceted roles of IL-15 with regard to the main immunological processes involved in the pathogenesis of celiac disease.
Subject(s)
Celiac Disease/immunology , Celiac Disease/metabolism , Interleukin-15/metabolism , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Celiac Disease/genetics , Gene Expression Regulation , Homeostasis , Humans , Immune Tolerance , Interleukin-15/genetics , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Signal Transduction , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolismSubject(s)
B-Lymphocytes/immunology , Celiac Disease/immunology , Intestinal Mucosa/immunology , Intestines/immunology , Intestines/pathology , Animals , Atrophy , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Disease Models, Animal , Glutens/adverse effects , HLA-DQ Antigens/immunology , Interferon-gamma/immunology , Mice , Protein Glutamine gamma Glutamyltransferase 2/immunologyABSTRACT
BACKGROUND & AIMS: The mechanisms of tissue destruction during progression of celiac disease are poorly defined. It is not clear how tissue stress and adaptive immunity contribute to the activation of intraepithelial cytotoxic T cells and the development of villous atrophy. We analyzed epithelial cells and intraepithelial cytotoxic T cells in family members of patients with celiac disease, who were without any signs of adaptive antigluten immunity, and in potential celiac disease patients, who have antibodies against tissue transglutaminase 2 in the absence of villous atrophy. METHODS: We collected blood and intestinal biopsy specimens from 268 patients at tertiary medical centers in the United States and Italy from 2004 to 2012. All subjects had normal small intestinal histology. Study groups included healthy individuals with no family history of celiac disease or antibodies against tissue transglutaminase 2 (controls), healthy family members of patients with celiac disease, and potential celiac disease patients. Intraepithelial cytotoxic T cells were isolated and levels of inhibitory and activating natural killer (NK) cells were measured by flow cytometry. Levels of heat shock protein (HSP) and interleukin 15 were measured by immunohistochemistry, and ultrastructural alterations in intestinal epithelial cells (IECs) were assessed by electron microscopy. RESULTS: IECs from subjects with a family history of celiac disease, but not from subjects who already had immunity to gluten, expressed higher levels of HS27, HSP70, and interleukin-15 than controls; their IECs also had ultrastructural alterations. Intraepithelial cytotoxic T cells from relatives of patients with celiac disease expressed higher levels of activating NK receptors than cells from controls, although at lower levels than patients with active celiac disease, and without loss of inhibitory receptors for NK cells. Intraepithelial cytotoxic T cells from potential celiac disease patients failed to up-regulate activating NK receptors. CONCLUSIONS: A significant subset of healthy family members of patients with celiac disease with normal intestinal architecture had epithelial alterations, detectable by immunohistochemistry and electron microscopy. The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with active celiac disease.
Subject(s)
Adaptive Immunity , Celiac Disease/immunology , Cell Communication , Epithelial Cells/immunology , Intestinal Mucosa/immunology , Intestine, Small/immunology , Stress, Physiological , T-Lymphocytes, Cytotoxic/immunology , Autoantibodies/blood , Case-Control Studies , Celiac Disease/blood , Celiac Disease/pathology , Epithelial Cells/metabolism , Epithelial Cells/ultrastructure , GTP-Binding Proteins/immunology , HSP27 Heat-Shock Proteins/immunology , HSP27 Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/immunology , HSP70 Heat-Shock Proteins/metabolism , Heat-Shock Proteins , Humans , Interleukin-15/immunology , Interleukin-15/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/ultrastructure , Intestine, Small/metabolism , Intestine, Small/ultrastructure , Italy , Molecular Chaperones , Phenotype , Protein Glutamine gamma Glutamyltransferase 2 , Risk Factors , Signal Transduction , T-Lymphocytes, Cytotoxic/metabolism , T-Lymphocytes, Cytotoxic/ultrastructure , Transglutaminases/immunology , United StatesABSTRACT
Strategies that modulate antigen delivery are being tested to reverse autoimmunity.
Subject(s)
Autoantigens , Autoimmune Diseases , Desensitization, Immunologic , Self Tolerance , Autoimmunity , Autoimmune Diseases/therapy , Autoantigens/administration & dosage , Autoantigens/immunology , Antigen-Presenting Cells/immunology , Antigen Presentation , Desensitization, Immunologic/methods , Humans , Animals , MiceABSTRACT
Early immune response to the largely used Mycobacterium bovis bacillus Calmette-Guérin (BCG) intradermal vaccine remains ill defined. Three days after BCG inoculation into the mouse ear, in addition to neutrophils infiltrating skin, we observed CD11b(+)Ly-6C(int)Ly-6G(-) myeloid cells. Neutrophil depletion markedly enhanced their recruitment. These cells differed from inflammatory monocytes and required MyD88-dependent BCG-specific signals to invade skin, whereas neutrophil influx was MyD88 independent. Upon BCG phagocytosis, CD11b(+)Ly-6C(int)Ly-6G(-) cells produced NO, which required the IL-1 receptor. Despite NO production, they were unable to kill BCG or the nonpathogenic Mycobacterium smegmatis. However, they markedly impaired T cell priming in the draining lymph node. Their elimination by all-trans retinoid acid treatment increased the number of IFN-gamma-producing CD4 T cells. Thus, BCG vaccination recruits innate myeloid-derived suppressor cells, akin to mouse tumor-infiltrating cells. These propathogenic cells dampen the early T cell response and might facilitate BCG persistence.
Subject(s)
BCG Vaccine/administration & dosage , BCG Vaccine/immunology , Cell Movement/immunology , Lymphocyte Activation/immunology , Myeloid Cells/immunology , Nitric Oxide/biosynthesis , Receptors, Interleukin-1/physiology , T-Lymphocyte Subsets/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , Female , Immunity, Innate , Lymph Nodes/immunology , Lymph Nodes/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myeloid Cells/cytology , Neutrophils/immunology , Neutrophils/pathology , Nitric Oxide/physiology , Receptors, Interleukin-1/antagonists & inhibitors , T-Lymphocyte Subsets/pathologyABSTRACT
The design and use of mouse models that reproduce key features of human diseases are critical to advance our understanding of the pathogenesis of autoimmune diseases and to test new therapeutic strategies. Celiac disease is a unique organ-specific autoimmune-like disorder occurring in genetically susceptible individuals carrying HLA-DQ2 or HLA-DQ8 molecules who consume gluten. The key histological characteristic of the disease in humans is the destruction of the lining of the small intestine, a feature that has been difficult to reproduce in immunocompetent animal models. This unit describes the DQ8-Dd -villin-IL-15 transgenic mouse model of CeD, which was engineered based on the knowledge acquired from studying CeD patients' intestinal samples, and which represents the first animal model that develops villous atrophy in an HLA- and gluten-dependent manner without administration of any adjuvant. We provide detailed protocols for inducing and monitoring intestinal tissue damage, evaluating the cytotoxic properties of intraepithelial lymphocytes that mediate enterocyte lysis, and assessing the activation of the enzyme transglutaminase 2, which contributes to the generation of highly immunogenic gluten peptides. Detailed protocols to prepare pepsin-trypsin digested gliadin (PT-gliadin) or chymotrypsin-digested gliadin (CT-gliadin), which allow antibody detection against native or deamidated gluten peptides, are also provided in this unit. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Induction of celiac-like disease in DQ8-Dd -villin-IL-15tg mice Basic Protocol 2: Histological assessment of villous atrophy Support Protocol 1: Morphometric assessment of villous/crypt ratio Support Protocol 2: Evaluation of epithelial cells renewal Support Protocol 3: Evaluation of the density of intraepithelial lymphocytes Basic Protocol 3: Analysis of cytotoxic intraepithelial lymphocytes Basic Protocol 4: Transglutaminase 2 activation and measurement of antibodies against native and deamidated gluten peptides Support Protocol 4: Preparation of CT-gliadin Support Protocol 5: Preparation of PT-gliadin.
Subject(s)
Celiac Disease , Animals , Atrophy , Celiac Disease/diagnosis , Disease Models, Animal , Gliadin , Glutens , Humans , Mice , Mice, TransgenicABSTRACT
Several environmental, genetic, and immune factors create a "perfect storm" for the development of coeliac disease: the antigen gluten, the strong association of coeliac disease with HLA, the deamidation of gluten peptides by the enzyme transglutaminase 2 (TG2) generating peptides that bind strongly to the predisposing HLA-DQ2 or HLA-DQ8 molecules, and the ensuing unrestrained T cell response. T cell immunity is at the center of the disease contributing to the inflammatory process through the loss of tolerance to gluten and the differentiation of HLA-DQ2 or HLA-DQ8-restricted anti-gluten inflammatory CD4+ T cells secreting pro-inflammatory cytokines and to the killing of intestinal epithelial cells by cytotoxic intraepithelial CD8+ lymphocytes. However, recent studies emphasize that the individual contribution of each of these cell subsets is not sufficient and that interactions between these different populations of T cells and the simultaneous activation of innate and adaptive immune pathways in distinct gut compartments are required to promote disease immunopathology. In this review, we will discuss how tissue destruction in the context of coeliac disease results from the complex interactions between gluten, HLA molecules, TG2, and multiple innate and adaptive immune components.
Subject(s)
Adaptive Immunity/immunology , Celiac Disease/immunology , Glutens/immunology , HLA Antigens/immunology , Immunity, Innate/immunology , Animals , Celiac Disease/pathology , GTP-Binding Proteins/immunology , Humans , Protein Glutamine gamma Glutamyltransferase 2 , Transglutaminases/immunologyABSTRACT
Interleukin-17 (IL-17)-producing γδ (γδ17) T cells are innate-like lymphocytes that contribute to protective anti-microbial responses but are also implicated in pathogenic inflammation at barrier sites. Understanding tissue-specific signals that regulate this subset is important to boost host defense mechanisms, but also to mitigate immunopathology. Here, we demonstrate that prostaglandin E2 (PGE2), a cyclooxygenase-dependent member of the eicosanoid family, directly enhances cytokine production by circulating and tissue-specific γδ17 T cells in vitro. Gain- and loss-of-function in vivo approaches further reveal that although provision of PGE2 amplifies psoriasiform inflammation, ablation of host mPGES1-dependent PGE2 synthesis is dispensable for cutaneous γδ17 T cell activation. By contrast, loss of endogenous PGE2 production or depletion of the gut microbiota compromises intestinal γδ17 T cell responses and increases disease severity during experimental colitis. Together, our results demonstrate how a lipid mediator can synergize with tissue-specific signals to enhance innate lymphocyte production of IL-17 during barrier inflammation.
Subject(s)
Dinoprostone/pharmacology , Inflammation/metabolism , Interleukin-17/biosynthesis , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Skin/pathology , Animals , Colitis/chemically induced , Dextran Sulfate , Female , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Male , Mice, Inbred C57BL , Prostaglandin-E Synthases/metabolism , Receptors, Antigen, T-Cell, gamma-delta/drug effectsABSTRACT
Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.
Subject(s)
Antigens/immunology , Celiac Disease/immunology , Celiac Disease/virology , Glutens/immunology , Inflammation/virology , Reoviridae Infections/complications , Reoviridae Infections/immunology , Th1 Cells/immunology , Animals , Diet/adverse effects , Disease Models, Animal , Genetic Engineering , Humans , Immune Tolerance , Inflammation/immunology , Interferon Regulatory Factor-1/genetics , Interferon Regulatory Factor-1/immunology , Interferon Type I/genetics , Interferon Type I/immunology , Intestines/immunology , Intestines/pathology , Intestines/virology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptor, Interferon alpha-beta/genetics , Reoviridae/geneticsABSTRACT
BACKGROUND: Mycobacteriophage Ms6 integrates into Mycobacterium smegmatis and M. bovis BCG chromosome at the 3' end of tRNAala genes. Homologous recombination occurs between the phage attP core and the attB site located in the T-loop. Integration-proficient vectors derived from Ms6 are useful genetic tools, but their insertion sites in the BCG chromosome remain poorly defined. The primary objective of this study was to identify Ms6 target genes in M. smegmatis and BCG. We then aimed to modify the attP site in Ms6-derived vectors, to switch integration to other tRNAala loci. This provided the basis for the development of recombinant M. bovis BCG strains expressing several reporter genes inserted into different tRNAala genes. RESULTS: The three tRNAala genes are highly conserved in M. smegmatis and BCG. However, in the T-loop of tRNAalaU and tRNAalaV containing the attB site, a single base difference was observed between the two species. We observed that the tRNAalaU gene was the only site into which Ms6-derived integration-proficient vectors integrated in M. smegmatis, whereas in BCG, the tRNAalaV gene was used as the target. No integration occurred in the BCG tRNAalaU T-loop, despite a difference of only one base from the 26-base Ms6 attP core. We mutated the attP core to give a perfect match with the other tRNAala T-loops from M. smegmatis and BCG. Modification of the seven-base T-loop decreased integration efficiency, identifying this site as a possible site of strand exchange. Finally, two Ms6 vectors were constructed to integrate two reporter genes into the tRNAalaU and tRNAalaV T-loops of the same BCG chromosome. CONCLUSION: Small changes in the 7 bp T-loop attP site of Ms6 made it possible to use another attB site, albeit with a lower integration efficiency. These molecular studies on BCG tRNAala genes made it possible to create valuable tools for the site-directed insertion of several genes in the same BCG strain. These tools will be useful for the development of novel multivalent vaccines and genetic studies.
Subject(s)
Attachment Sites, Microbiological/genetics , Mycobacteriophages/physiology , Mycobacterium/genetics , RNA, Transfer, Ala/genetics , Virus Integration/physiology , Base Sequence , DNA, Bacterial/metabolism , DNA, Recombinant , Molecular Sequence Data , Mutagenesis, Site-Directed , Mycobacterium bovis/genetics , Mycobacterium smegmatis/genetics , Organisms, Genetically Modified , Sequence Homology, Nucleic Acid , Transformation, Bacterial/physiologySubject(s)
Celiac Disease/pathology , Disease Models, Animal , Intestinal Mucosa/pathology , Mice , Adaptive Immunity/physiology , Animals , Atrophy/complications , Atrophy/immunology , Celiac Disease/complications , Celiac Disease/genetics , Celiac Disease/immunology , Glutens/immunology , HLA-DQ Antigens/genetics , HLA-DQ Antigens/immunology , Humans , Interleukin-15/genetics , Interleukin-15/metabolism , Intestinal Mucosa/metabolism , Up-RegulationABSTRACT
In this Opinion article, we discuss the function of tissues as a crucial checkpoint for the regulation of effector T cell responses, and the notion that interleukin-15 (IL-15) functions as a danger molecule that communicates to the immune system that the tissue is under attack and poises it to mediate tissue destruction. More specifically, we propose that expression of IL-15 in tissues promotes T helper 1 cell-mediated immunity and provides co-stimulatory signals to effector cytotoxic T cells to exert their effector functions and drive tissue destruction. Therefore, we think that IL-15 contributes to tissue protection by promoting the elimination of infected cells but that when its expression is chronically dysregulated, it can promote the development of complex T cell-mediated disorders associated with tissue destruction, such as coeliac disease and type 1 diabetes.
Subject(s)
Immunity, Cellular/immunology , Interleukin-15/immunology , Signal Transduction/immunology , T-Lymphocytes/immunology , Bacterial Infections/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Celiac Disease/immunology , Celiac Disease/metabolism , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Humans , Interleukin-15/metabolism , Interleukin-15 Receptor alpha Subunit/immunology , Interleukin-15 Receptor alpha Subunit/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Models, Immunological , Protein Binding/immunology , T-Lymphocytes/metabolism , Th1 Cells/immunology , Th1 Cells/metabolismABSTRACT
Eicosanoids are inflammatory mediators that play a key but incompletely understood role in linking the innate and adaptive immune systems. Here, we show that cytotoxic effector T cells (CTLs) are capable of both producing and responding to cysteinyl leukotrienes (CystLTs), allowing for the killing of target cells in a T cell receptor-independent manner. This process is dependent on the natural killer receptor NKG2D and exposure to IL-15, a cytokine induced in distressed tissues. IL-15 and NKG2D signaling drives the up-regulation of key enzymes implicated in the synthesis of CystLTs, as well as the expression of CystLT receptors, suggesting a positive feedback loop. Finally, although the CystLT pathway has been previously linked to various allergic disorders, we provide unexpected evidence for its involvement in the pathogenesis of celiac disease (CD), a T helper 1 cell-mediated enteropathy induced by gluten. These findings provide new insights into the cytolytic signaling pathway of NKG2D and the pathogenesis of organ-specific immune disorders. Furthermore, they suggest that the blockade of CystLT receptors may represent a potent therapeutic target for CD or potentially other autoimmune disorders in which NKG2D has been implicated.
Subject(s)
Celiac Disease/immunology , Cysteine/metabolism , Interleukin-15/immunology , Leukotrienes/metabolism , NK Cell Lectin-Like Receptor Subfamily K/immunology , T-Lymphocytes, Cytotoxic/immunology , Adult , Arachidonate 5-Lipoxygenase/genetics , Arachidonate 5-Lipoxygenase/metabolism , Case-Control Studies , Celiac Disease/physiopathology , Cells, Cultured , Cysteine/immunology , Female , Humans , Interleukin-15/metabolism , Leukotrienes/immunology , Male , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Receptors, Leukotriene/genetics , Receptors, Leukotriene/metabolism , Th1 Cells/immunology , Th1 Cells/metabolism , Up-RegulationABSTRACT
NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase.
Subject(s)
Arthritis, Psoriatic/immunology , Gene Expression Regulation/immunology , Interleukin-15/immunology , Killer Cells, Natural/immunology , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Phospholipases A2, Cytosolic/metabolism , Signal Transduction/immunology , Arthritis, Psoriatic/metabolism , Cytokines/genetics , Cytokines/metabolism , Flow Cytometry , Humans , Immunohistochemistry , Interleukin-15/metabolism , Killer Cells, Natural/metabolism , RNA, Small Interfering/genetics , TransfectionABSTRACT
Celiac disease is a T cell-mediated immune disorder induced by dietary gluten that is characterized by the development of an inflammatory anti-gluten CD4 T cell response, anti-gluten antibodies, and autoantibodies against tissue transglutaminase 2 and the activation of intraepithelial lymphocytes (IELs) leading to the destruction of the intestinal epithelium. Intraepithelial lymphocytes represent a heterogeneous population of T cells composed mainly of cytotoxic CD8 T cells residing within the epithelial layer, whose main role is to maintain the integrity of the epithelium by eliminating infected cells and promoting epithelial repair. Dysregulated activation of IELs is a hallmark of CD and is critically involved in epithelial cell destruction and the subsequent development of villous atrophy. In this review, we compare and contrast the phenotype and function of human and mouse small intestinal IELs under physiological conditions. Furthermore, we discuss how conditions of epithelial distress associated with overexpression of IL-15 and non-classical MHC class I molecules induce cytotoxic IELs to become licensed killer cells that upregulate activating NKG2D and CD94/NKG2C natural killer receptors, acquiring lymphokine killer activity. Pathways leading to dysregulated IEL activation could eventually be targeted to prevent villous atrophy and treat patients who respond poorly to gluten-free diet.
Subject(s)
Celiac Disease/immunology , Intestinal Mucosa/immunology , Lymphocytes/immunology , Animals , Celiac Disease/metabolism , Homeostasis/immunology , Humans , Intestinal Mucosa/metabolism , Intestine, Small/immunology , Intestine, Small/metabolism , Lymphocytes/metabolism , Protein Glutamine gamma Glutamyltransferase 2ABSTRACT
BACKGROUND: Obtaining a certain multi-functionality of cellular immunity for the control of infectious diseases is a burning question in immunology and in vaccine design. Early events, including antigen shuttling to secondary lymphoid organs and recruitment of innate immune cells for adaptive immune response, determine host responsiveness to antigens. However, the sequence of these events and their impact on the quality of the immune response remain to be elucidated. Here, we chose to study Modified Vaccinia virus Ankara (MVA) which is now replacing live Smallpox vaccines and is proposed as an attenuated vector for vaccination strategies against infectious diseases. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed in vivo mechanisms triggered following intradermal (i.d.) and intramuscular (i.m.) Modified Vaccinia virus Ankara (MVA) administration. We demonstrated significant differences in the antigen shuttling to lymphoid organs by macrophages (MPhis), myeloid dendritic cells (DCs), and neutrophils (PMNs). MVA i.d. administration resulted in better antigen distribution and more sustained antigen-presenting cells (APCs) recruitment into draining lymph nodes than with i.m. administration. These APCs, which comprise both DCs and MPhis, were differentially involved in T cell priming and shaped remarkably the quality of cytokine-producing virus-specific T cells according to the entry route of MVA. CONCLUSIONS/SIGNIFICANCE: This study improves our understanding of the mechanisms of antigen delivery and their consequences on the quality of immune responses and provides new insights for vaccine development.