Formyl peptide receptor 2 (FPR2) is a receptor for formylated peptides and specific pro-resolving mediators, and is involved in various inflammatory processes. Here, we aimed to elucidate the role of FPR2 in dendritic cell (DC) function and autoimmunity-related central nervous system (CNS) inflammation by using the experimental autoimmune encephalomyelitis (EAE) model. EAE induction was accompanied by increased Fpr2 mRNA expression in the spinal cord. FPR2-deficient (Fpr2KO) mice displayed delayed onset of EAE compared to wild-type (WT) mice, associated with reduced frequencies of Th17 cells in the inflamed spinal cord at the early stage of the disease. However, FPR2 deficiency did not affect EAE severity after the disease reached its peak. FPR2 deficiency in mature DCs resulted in decreased expression of Th17 polarizing cytokines IL6, IL23p19, IL1β, and thereby diminished the DC-mediated activation of Th17 cell differentiation. LPS-activated FPR2-deficient DCs showed upregulated Nos2 expression and nitric oxide (NO) production, as well as reduced oxygen consumption rate and impaired mitochondrial function, including decreased mitochondrial superoxide levels, lower mitochondrial membrane potential and diminished expression of genes related to the tricarboxylic acid cycle and genes related to the electron transport chain, as compared to WT DCs. Treatment with a NO inhibitor reversed the reduced Th17 cell differentiation in the presence of FPR2-deficient DCs. Together, by regulating DC metabolism, FPR2 enhances the production of DC-derived Th17-polarizing cytokines and hence Th17 cell differentiation in the context of neuroinflammation.

• MeSH
• buněčná diferenciace * MeSH
• buňky Th17 * imunologie   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky * imunologie   metabolismus   MeSH
• encefalomyelitida autoimunitní experimentální * imunologie   metabolismus   MeSH
• mícha imunologie   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované * MeSH
• myši MeSH
• neurozánětlivé nemoci imunologie   metabolismus   MeSH
• receptory pro formylované peptidy * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

T cells are pivotal in the adaptive immune defense, necessitating a delicate balance between robust response against infections and self-tolerance. Their activation involves intricate cross-talk among signaling pathways triggered by the T-cell antigen receptors (TCR) and co-stimulatory or inhibitory receptors. The molecular regulation of these complex signaling networks is still incompletely understood. Here, we identify the adaptor protein ABIN1 as a component of the signaling complexes of GITR and OX40 co-stimulation receptors. T cells lacking ABIN1 are hyper-responsive ex vivo, exhibit enhanced responses to cognate infections, and superior ability to induce experimental autoimmune diabetes in mice. ABIN1 negatively regulates p38 kinase activation and late NF-κB target genes. P38 is at least partially responsible for the upregulation of the key effector proteins IFNG and GZMB in ABIN1-deficient T cells after TCR stimulation. Our findings reveal the intricate role of ABIN1 in T-cell regulation.

• MeSH
• adaptorové proteiny signální transdukční * metabolismus   genetika   MeSH
• aktivace lymfocytů imunologie   genetika   MeSH
• cytotoxické T-lymfocyty * imunologie   metabolismus   MeSH
• diabetes mellitus 1. typu imunologie   genetika   metabolismus   MeSH
• glukokortikoidy indukovaný protein související s TNRF MeSH
• interferon gama metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• receptory OX40 metabolismus   genetika   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C to mediate its stability, glycosylation and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17R signaling complex. Accordingly, CMTM4-deficient mice had a severe defect in the recruitment of immune cells following IL-17A administration and were largely resistant to experimental psoriasis, but not to experimental autoimmune encephalomyelitis. Collectively, our data identified CMTM4 as an essential component of IL-17R and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.

• MeSH
• encefalomyelitida autoimunitní experimentální * genetika   MeSH
• interleukin-17 metabolismus   MeSH
• lidé MeSH
• myši MeSH
• proteiny obsahující MARVEL doménu genetika   MeSH
• psoriatická artritida * MeSH
• psoriáza * MeSH
• receptory interleukinu-17 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Mature T cells are selected for recognizing self-antigens with low to intermediate affinity in the thymus. Recently, the relative differences in self-reactivity among individual T-cell clones were appreciated as important factors regulating their fate and immune response, but the role of self-reactivity in T-cell biology is incompletely understood. We addressed the role of self-reactivity in T-cell diversity by generating an atlas of mouse peripheral CD8+ T cells, which revealed two unconventional populations of antigen-inexperienced T cells. In the next step, we examined the steady-state phenotype of monoclonal T cells with various levels of self-reactivity. Highly self-reactive clones preferentially differentiate into antigen-inexperienced memory-like cells, but do not form a population expressing type I interferon-induced genes, showing that these two subsets have unrelated origins. The functional comparison of naïve monoclonal CD8+ T cells specific to the identical model antigen did not show any correlation between the level of self-reactivity and the magnitude of the immune response.

• MeSH
• autoantigeny MeSH
• buněčné klony MeSH
• CD8-pozitivní T-lymfocyty * MeSH
• interferon typ I * MeSH
• myši MeSH
• thymus MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of this study was to find out whether protease inhibitor 9 (PI-9) and granzyme B (GrB) molecules that contribute to immune response and the immunological privilege of various tissues are expressed in healthy and pathological human corneas. Using cryosections, cell imprints of control corneoscleral discs, we showed that PI-9 was expressed particularly in the endothelium, the superficial and suprabasal epithelium of healthy corneas, limbus, and conjunctiva. GrB was localized in healthy corneal and conjunctival epithelium, while the endothelium showed weak immunostaining. The expression of PI-6 and GrB was confirmed by qRT-PCR. Increased expression levels of the PI-9 and GrB genes were determined when the corneas were cultured with proinflammatory cytokines. Fluorescent and enzymatic immunohistochemistry of pathological corneal explants (corneal melting and herpes virus keratitis) showed pronounced PI-9, GrB, human leucocyte antigen (HLA)-DR, and leukocyte-common antigen (CD45) signals localized in multicellular stromal infiltrates and inflammatory cells scattered in the corneal stroma. We conclude that increased expression of the PI-9 and GrB proteins under pathological conditions and their upregulation in an inflammatory environment indicate their participation in immune response of the cornea during the inflammatory process.

• Publikační typ
• časopisecké články MeSH

• Publikační typ
• abstrakt z konference MeSH

Experimental autoimmune encephalomyelitis (EAE) represents the mouse model of multiple sclerosis, a devastating neurological disorder. EAE development and progression involves the infiltration of different immune cells into the brain and spinal cord. However, less is known about a potential role of eosinophil granulocytes for EAE disease pathogenesis. In the present study, we found enhanced eosinophil abundance accompanied by increased concentration of the eosinophil chemoattractant eotaxin-1 in the spinal cord in the course of EAE induced in C57BL/6 mice by immunization with MOG35-55 peptide. However, the absence of eosinophils did not affect neuroinflammation, demyelination and clinical development or severity of EAE, as assessed in ∆dblGATA1 eosinophil-deficient mice. Taken together, despite their enhanced abundance in the inflamed spinal cord during disease progression, eosinophils were dispensable for EAE development.

• MeSH
• chemokin CCL11 metabolismus   MeSH
• encefalomyelitida autoimunitní experimentální krev   diagnóza   imunologie   patologie   MeSH
• eozinofily imunologie   metabolismus   MeSH
• glykoprotein v myelinu oligodendrocytů aplikace a dávkování   imunologie   MeSH
• lidé MeSH
• mícha imunologie   patologie   MeSH
• myši transgenní MeSH
• myši MeSH
• peptidové fragmenty aplikace a dávkování   imunologie   MeSH
• roztroušená skleróza krev   diagnóza   imunologie   patologie   MeSH
• stupeň závažnosti nemoci MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Ag-inexperienced memory-like T (AIMT) cells are functionally unique T cells, representing one of the two largest subsets of murine CD8+ T cells. However, differences between laboratory inbred strains, insufficient data from germ-free mice, a complete lack of data from feral mice, and an unclear relationship between AIMT cells formation during aging represent major barriers for better understanding of their biology. We performed a thorough characterization of AIMT cells from mice of different genetic background, age, and hygienic status by flow cytometry and multiomics approaches, including analyses of gene expression, TCR repertoire, and microbial colonization. Our data showed that AIMT cells are steadily present in mice, independent of their genetic background and hygienic status. Despite differences in their gene expression profiles, young and aged AIMT cells originate from identical clones. We identified that CD122 discriminates two major subsets of AIMT cells in a strain-independent manner. Whereas thymic CD122LOW AIMT cells (innate memory) prevail only in young animals with high thymic IL-4 production, peripheral CD122HIGH AIMT cells (virtual memory) dominate in aged mice. Cohousing with feral mice changed the bacterial colonization of laboratory strains but had only minimal effects on the CD8+ T cell compartment, including AIMT cells.

• MeSH
• antigeny genetika   imunologie   MeSH
• fenotyp MeSH
• imunologická paměť genetika   imunologie   MeSH
• klonální evoluce MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• nestabilita genomu MeSH
• stárnutí genetika   imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND & AIMS: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autoimmune disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, but patients also develop intestinal disorders. APECED is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE, which regulates immune tolerance) that allow self-reactive T cells to enter the periphery. Enteric α-defensins are antimicrobial peptides secreted by Paneth cells. Patients with APECED frequently have gastrointestinal symptoms and seroreactivity against secretory granules of Paneth cells. We investigated whether enteric α-defensins are autoantigens in humans and mice with AIRE deficiency. METHODS: We analyzed clinical data, along with serum and stool samples and available duodenal biopsies from 50 patients with APECED collected from multiple centers in Europe. Samples were assessed for expression of defensins and other molecules by quantitative reverse transcription polymerase chain reaction and flow cytometry; levels of antibodies and other proteins were measured by immunohistochemical and immunoblot analyses. Histologic analyses were performed on biopsy samples. We used Aire(-/-) mice as a model of APECED, and studied the effects of transferring immune cells from these mice to athymic mice. RESULTS: Enteric defensins were detected in extraintestinal tissues of patients with APECED, especially in medullary thymic epithelial cells. Some patients with APECED lacked Paneth cells and were seropositive for defensin-specific autoantibodies; the presence of autoantibodies correlated with frequent diarrhea. Aire(-/-) mice developed defensin-specific T cells. Adoptive transfer of these T cells to athymic mice resulted in T-cell infiltration of the gut, loss of Paneth cells, microbial dysbiosis, and the induction of T-helper 17 cell-mediated autoimmune responses resembling those observed in patients with APECED. CONCLUSIONS: In patients with APECED, loss of AIRE appears to cause an autoimmune response against enteric defensins and loss of Paneth cells. Aire(-/-) mice developed defensin-specific T cells that cause intestinal defects similar to those observed in patients with APECED. These findings provide a mechanism by which loss of AIRE-mediated immune tolerance leads to intestinal disorders in patients with APECED.

• MeSH
• alfa-defensiny imunologie   MeSH
• autoimunita * MeSH
• autoimunitní polyglandulární syndromy komplikace   imunologie   MeSH
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• předškolní dítě MeSH
• senioři MeSH
• střeva imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• transkripční faktory genetika   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Type 1 Diabetes (T1D) is considered to be a T-helper- (Th-) 1 autoimmune disease; however, T1D pathogenesis likely involves many factors, and sufficient tools for autoreactive T cell detection for the study of this disease are currently lacking. In this study, using gene expression microarrays, we analysed the effect of diabetes-associated autoantigens on peripheral blood mononuclear cells (PBMCs) with the purpose of identifying (pre)diabetes-associated cell processes. Twelve patients with recent onset T1D, 18 first-degree relatives of the TD1 patients (DRL; 9/18 autoantibody positive), and 13 healthy controls (DV) were tested. PBMCs from these individuals were stimulated with a cocktail of diabetes-associated autoantigens (proinsulin, IA-2, and GAD65-derived peptides). After 72 hours, gene expression was evaluated by high-density gene microarray. The greatest number of functional differences was observed between relatives and controls (69 pathways), from which 15% of the pathways belonged to "immune response-related" processes. In the T1D versus controls comparison, more pathways (24%) were classified as "immune response-related." Important pathways that were identified using data from the T1D versus controls comparison were pathways involving antigen presentation by MHCII, the activation of Th17 and Th22 responses, and cytoskeleton rearrangement-related processes. Genes involved in Th17 and TGF-beta cascades may represent novel, promising (pre)diabetes biomarkers.

• MeSH
• autoantigeny imunologie   metabolismus   MeSH
• autoprotilátky imunologie   metabolismus   MeSH
• diabetes mellitus 1. typu genetika   imunologie   metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• exprese genu MeSH
• leukocyty mononukleární imunologie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• prediabetes genetika   imunologie   metabolismus   MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH