294 results on '"Physiology"'
Search Results
2. Keratinocyte-intrinsic MHCII expression controls microbiota-induced Th1 cell responses.
- Author
-
Tamoutounour, Samira, Seong-Ji Han, Deckers, Julie, Constantinides, Michael G., Hurabielle, Charlotte, Harrison, Oliver J., Bouladoux, Nicolas, Linehan, Jonathan L., Link, Verena M., Vujkovic-Cvijin, Ivan, Perez-Chaparro, Paula Juliana, Rosshart, Stephan P., Rehermann, Barbara, Lazarevic, Vanja, and Belkaid, Yasmine
- Subjects
- *
TH1 cells , *T cells , *ANTIGEN presentation , *PHYSIOLOGY - Abstract
The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22–mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A–producing CD4+ T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissuespecific rules governing the dialogue between a host and its microbiota. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
3. Anti-ganglioside antibodies in patients with Zika virus infection-associated Guillain-Barré Syndrome in Brazil.
- Author
-
Rivera-Correa, Juan, de Siqueira, Isadora Cristina, Mota, Sabrina, do Rosário, Mateus Santana, Pereira de Jesus, Pedro Antônio, Alcantara, Luiz Carlos Junior, Ernst, Joel D., and Rodriguez, Ana
- Subjects
- *
ZIKA virus , *GUILLAIN-Barre syndrome , *ZIKA virus infections , *IMMUNOGLOBULINS , *ANTIGEN presentation - Abstract
Zika virus infection is associated with the development of Guillain-Barré syndrome (GBS), a neurological autoimmune disorder caused by immune recognition of gangliosides and other components at nerve membranes. Using a high-throughput ELISA, we have analyzed the anti-glycolipid antibody profile, including gangliosides, of plasma samples from patients with Zika infections associated or not with GBS in Salvador, Brazil. We have observed that Zika patients that develop GBS present higher levels of anti-ganglioside antibodies when compared to Zika patients without GBS. We also observed that a broad repertoire of gangliosides was targeted by both IgM and IgG anti-self antibodies in these patients. Since Zika virus infects neurons, which contain membrane gangliosides, antigen presentation of these infected cells may trigger the observed autoimmune anti-ganglioside antibodies suggesting direct infection-induced autoantibodies as a cause leading to GBS development. Collectively, our results establish a link between anti-ganglioside antibodies and Zika-associated GBS in patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
4. Whole blood transcriptomic profiles can differentiate vulnerability to chronic low back pain.
- Author
-
Dorsey, Susan G., Renn, Cynthia L., Griffioen, Mari, Lassiter, Cameron B., Zhu, Shijun, Huot-Creasy, Heather, McCracken, Carrie, Mahurkar, Anup, Shetty, Amol C., Jackson-Cook, Colleen K., Kim, Hyungsuk, Henderson, Wendy A., Saligan, Leorey, Gill, Jessica, Colloca, Luana, Lyon, Debra E., and Starkweather, Angela R.
- Subjects
- *
LUMBAR pain , *MAJOR histocompatibility complex , *CHRONIC pain , *OXIDATIVE phosphorylation , *ANTIGEN presentation , *COMPUTATIONAL biology - Abstract
The mechanisms underlying the transition from acute to chronic pain remain unclear. Here, we sought to characterize the transcriptome associated with chronic low back pain as well as the transcriptome of the transition from acute to chronic low back pain. For the analysis, we compared the whole blood transcriptome of: (a) patients at the onset of low back pain who no longer had pain within 6 weeks after onset (acute) with patients who developed chronic low back pain at 6 months (chronic T5); and, (b) patients at the onset of low back pain (chronic T1) who developed chronic pain at 6 months with healthy pain-free (normal) controls. The majority of differentially expressed genes were protein coding. We illustrate a unique chronic low back pain transcriptome characterized by significant enrichment for known pain genes, extracellular matrix genes, and genes from the extended major histocompatibility complex (MHC) genomic locus. The transcriptome of the transition from acute to chronic low back pain was characterized by significant upregulation of antigen presentation pathway (MHC class I and II) genes and downregulation of mitochondrial genes associated with oxidative phosphorylation, suggesting a unique genomic signature of vulnerability to low back pain chronicity. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
5. Association of HLA class I type with prevalence and outcome of patients with acute myeloid leukemia and mutated nucleophosmin.
- Author
-
Kuželová, Kateřina, Brodská, Barbora, Schetelig, Johannes, Röllig, Christoph, Ráčil, Zdeněk, Walz, Juliane Stickel, Helbig, Grzegorz, Fuchs, Ota, Vraná, Milena, Pecherková, Pavla, Šálek, Cyril, and Mayer, Jiří
- Subjects
- *
NUCLEOPHOSMIN , *HLA histocompatibility antigens , *ACUTE myeloid leukemia , *IMMUNOSUPPRESSIVE agents , *IMMUNOPHARMACOLOGY - Abstract
Acute myeloid leukemia with mutated nucleophosmin (NPMc+ AML) forms a distinct AML subgroup with better prognosis which can potentially be associated with immune response against the mutated nucleophosmin (NPM). As the T-cell-mediated immunity involves antigen presentation on HLA class I molecules, we hypothesized that individuals with suitable HLA type could be less prone to develop NPMc+ AML. We compared HLA class I distribution in NPMc+ AML patient cohort (398 patients from 5 centers) with the HLA allele frequencies of the healthy population and found HLA-A*02, B*07, B*40 and C*07 underrepresented in the NPMc+ AML group. Presence of B*07 or C*07:01 antigen was associated with better survival in patients without concomitant FLT3 internal tandem duplication. Candidate NPM-derived immunopeptides were found for B*40 and B*07 using prediction software tools. Our findings suggest that a T-cell-mediated immune response could actually explain better prognosis of NPMc+ patients and provide a rationale for attempts to explore the importance of immunosuppressive mechanisms in this AML subgroup. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
6. Systematically benchmarking peptide-MHC binding predictors: From synthetic to naturally processed epitopes.
- Author
-
Zhao, Weilong and Sher, Xinwei
- Subjects
- *
MACHINE learning , *EPITOPES , *T cells , *CLINICAL immunology , *HLA histocompatibility antigens - Abstract
A number of machine learning-based predictors have been developed for identifying immunogenic T-cell epitopes based on major histocompatibility complex (MHC) class I and II binding affinities. Rationally selecting the most appropriate tool has been complicated by the evolving training data and machine learning methods. Despite the recent advances made in generating high-quality MHC-eluted, naturally processed ligandome, the reliability of new predictors on these epitopes has yet to be evaluated. This study reports the latest benchmarking on an extensive set of MHC-binding predictors by using newly available, untested data of both synthetic and naturally processed epitopes. 32 human leukocyte antigen (HLA) class I and 24 HLA class II alleles are included in the blind test set. Artificial neural network (ANN)-based approaches demonstrated better performance than regression-based machine learning and structural modeling. Among the 18 predictors benchmarked, ANN-based mhcflurry and nn_align perform the best for MHC class I 9-mer and class II 15-mer predictions, respectively, on binding/non-binding classification (Area Under Curves = 0.911). NetMHCpan4 also demonstrated comparable predictive power. Our customization of mhcflurry to a pan-HLA predictor has achieved similar accuracy to NetMHCpan. The overall accuracy of these methods are comparable between 9-mer and 10-mer testing data. However, the top methods deliver low correlations between the predicted versus the experimental affinities for strong MHC binders. When used on naturally processed MHC-ligands, tools that have been trained on elution data (NetMHCpan4 and MixMHCpred) shows better accuracy than pure binding affinity predictor. The variability of false prediction rate is considerable among HLA types and datasets. Finally, structure-based predictor of Rosetta FlexPepDock is less optimal compared to the machine learning approaches. With our benchmarking of MHC-binding and MHC-elution predictors using a comprehensive metrics, a unbiased view for establishing best practice of T-cell epitope predictions is presented, facilitating future development of methods in immunogenomics. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
7. A comprehensive in silico analysis for identification of therapeutic epitopes in HPV16, 18, 31 and 45 oncoproteins.
- Author
-
Panahi, Heidar Ali, Bolhassani, Azam, Javadi, Gholamreza, and Noormohammadi, Zahra
- Subjects
- *
PAPILLOMAVIRUSES , *EPITOPES , *DNA viruses , *VIRAL tropism , *ETIOLOGY of diseases , *EPITHELIAL cells - Abstract
Human papillomaviruses (HPVs) are a group of circular double-stranded DNA viruses, showing severe tropism to mucosal tissues. A subset of HPVs, especially HPV16 and 18, are the primary etiological cause for several epithelial cell malignancies, causing about 5.2% of all cancers worldwide. Due to the high prevalence and mortality, HPV-associated cancers have remained as a significant health problem in human society, making an urgent need to develop an effective therapeutic vaccine against them. Achieving this goal is primarily dependent on the identification of efficient tumor-associated epitopes, inducing a robust cell-mediated immune response. Previous information has shown that E5, E6, and E7 early proteins are responsible for the induction and maintenance of HPV-associated cancers. Therefore, the prediction of major histocompatibility complex (MHC) class I T cell epitopes of HPV16, 18, 31 and 45 oncoproteins was targeted in this study. For this purpose, a two-step plan was designed to identify the most probable CD8+ T cell epitopes. In the first step, MHC-I and II binding, MHC-I processing, MHC-I population coverage and MHC-I immunogenicity prediction analyses, and in the second step, MHC-I and II protein-peptide docking, epitope conservation, and cross-reactivity with host antigens’ analyses were carried out successively by different tools. Finally, we introduced five probable CD8+ T cell epitopes for each oncoprotein of the HPV genotypes (60 epitopes in total), which obtained better scores by an integrated approach. These predicted epitopes are valuable candidates for in vitro or in vivo therapeutic vaccine studies against the HPV-associated cancers. Additionally, this two-step plan that each step includes several analyses to find appropriate epitopes provides a rational basis for DNA- or peptide-based vaccine development. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
8. Short palate, lung, and nasal epithelial clone 1 (SPLUNC1) level determines steroid-resistant airway inflammation in aging
- Author
-
Amarjit Mishra, Amol Suryawanshi, Sangeet Makhija, Amit Kumar Mitra, Jyoti Yadav, Anil Kumar Jaiswal, and Maninder Sandey
- Subjects
Pulmonary and Respiratory Medicine ,Aging ,Physiology ,medicine.drug_class ,Dermatophagoides pteronyssinus ,Respiratory System ,Clone (cell biology) ,Inflammation ,airway inflammation ,Models, Biological ,Dexamethasone ,steroid-resistant asthma ,Immune system ,Cell Movement ,Physiology (medical) ,INTRODUCTION ,medicine ,Animals ,dendritic cells ,SPLUNC1 ,Glycoproteins ,Asthma ,Antigen Presentation ,Granuloma ,Lung ,business.industry ,Mediastinum ,Epithelial Cells ,Cell Biology ,Phosphoproteins ,Acquired immune system ,medicine.disease ,Pathophysiology ,respiratory tract diseases ,Eosinophils ,medicine.anatomical_structure ,Immunology ,Corticosteroid ,Steroids ,Lymph Nodes ,medicine.symptom ,business ,Glycolysis ,Research Article - Abstract
Asthma and its heterogeneity change with age. Increased airspace neutrophil numbers contribute to severe steroid-resistant asthma exacerbation in the elderly, which correlates with the changes seen in adults with asthma. However, whether that resembles the same disease mechanism and pathophysiology in aged and adults is poorly understood. Here, we sought to address the underlying molecular mechanism of steroid-resistant airway inflammation development and response to corticosteroid (Dex) therapy in aged mice. To study the changes in inflammatory mechanism, we used a clinically relevant treatment model of house-dust mite (HDM)-induced allergic asthma and investigated lung adaptive immune response in adult (20–22 wk old) and aged (80–82 wk old) mice. Our result indicates an age-dependent increase in airway hyperresponsiveness (AHR), mixed granulomatous airway inflammation comprising eosinophils and neutrophils, and Th1/Th17 immune response with progressive decrease in frequencies and numbers of HDM-bearing dendritic cells (DC) accumulation in the draining lymph node (DLn) of aged mice as compared with adult mice. RNA-Seq experiments of the aged lung revealed short palate, lung, and nasal epithelial clone 1 (SPLUNC1) as one of the steroid-responsive genes, which progressively declined with age and further by HDM-induced inflammation. Moreover, we found increased glycolytic reprogramming, maturation/activation of DCs, the proliferation of OT-II cells, and Th2 cytokine secretion with recombinant SPLUNC1 (rSPLUNC1) treatment. Our results indicate a novel immunomodulatory role of SPLUNC1 regulating metabolic adaptation/maturation of DC. An age-dependent decline in the SPLUNC1 level may be involved in developing steroid-resistant airway inflammation and asthma heterogeneity.
- Published
- 2022
9. Proteome-wide analysis of CD8+ T cell responses to EBV reveals differences between primary and persistent infection.
- Author
-
Forrest, Calum, Hislop, Andrew D., Rickinson, Alan B., and Zuo, Jianmin
- Subjects
- *
HERPESVIRUSES , *INFECTION , *HERPESVIRUS diseases , *PROTEOMICS , *T cells - Abstract
Human herpesviruses are antigenically rich agents that induce strong CD8+T cell responses in primary infection yet persist for life, continually challenging T cell memory through recurrent lytic replication and potentially influencing the spectrum of antigen-specific responses. Here we describe the first lytic proteome-wide analysis of CD8+ T cell responses to a gamma1-herpesvirus, Epstein-Barr virus (EBV), and the first such proteome-wide analysis of primary versus memory CD8+ T cell responses to any human herpesvirus. Primary effector preparations were generated directly from activated CD8+ T cells in the blood of infectious mononucleosis (IM) patients by in vitro mitogenic expansion. For memory preparations, EBV-specific cells in the blood of long-term virus carriers were first re-stimulated in vitro by autologous dendritic cells loaded with a lysate of lytically-infected cells, then expanded as for IM cells. Preparations from 7 donors of each type were screened against each of 70 EBV lytic cycle proteins in combination with the donor’s individual HLA class I alleles. Multiple reactivities against immediate early (IE), early (E) and late (L) lytic cycle proteins, including many hitherto unrecognised targets, were detected in both contexts. Interestingly however, the two donor cohorts showed a different balance between IE, E and L reactivities. Primary responses targeted IE and a small group of E proteins preferentially, seemingly in line with their better presentation on the infected cell surface before later-expressed viral evasins take full hold. By contrast, target choice equilibrates in virus carriage with responses to key IE and E antigens still present but with responses to a select subset of L proteins now often prominent. We infer that, for EBV at least, long-term virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
10. A mechanism of T cell dependent selection of antigen engaged Germinal Center B cells.
- Author
-
Krishna, Vinod and Bachman, Kurtis E.
- Subjects
- *
B cells , *GERMINAL centers , *T cells , *IMMUNOGLOBULIN producing cells , *LEUCOCYTES , *SPERM competition - Abstract
A model of B cell affinity selection is proposed, and an explanation of peripheral tolerance mechanisms through antibody repertoire editing is presented. We show that affinity discrimination between B cells is driven by a competition between obtaining T cell help and removal of B cells from the light zone, either through apoptosis or by a return to the dark zone of germinal centers. We demonstrate that this mechanism also allows for the negative selection of self reactive B cells and maintenance of B cell tolerance during the Germinal Center reaction. Finally, we demonstrate that clonal expansion upon return to the Germinal Center dark zone amplifies differences in the antigen affinity of B cells that survive the light zone. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
11. Paramunity-inducing Factors (PINDs) in dendritic cell (DC) cultures lead to impaired antileukemic functionality of DC-stimulated T-cells.
- Author
-
Ansprenger, Christian, Vogt, Valentin, Schick, Julia, Hirn-Lopez, Annika, Vokac, Yvonne, Harabacz, Ihor, Braeu, Marion, Kroell, Tanja, Karenberg, Axel, Kolb, Hans-Jochem, and Schmetzer, Helga
- Subjects
- *
DENDRITIC cells , *T cells , *VIRUS inactivation , *POXVIRUSES , *ANTIGEN presentation , *PHYSIOLOGY ,LEUKEMIA immunology - Abstract
Introduction Paramunity-inducing-Factors (PINDs) consist of attenuated/inactivated viruses of various poxvirus-genera, used in veterinary medicine as non-antigen-specific, non-immunising stimulators of the innate immune system against infectious and malignant diseases. Their danger-signaling-interactions were tested for their capacity to improve leukemic antigen-presentation on DC generated from AML-patients’ blasts (‘DC leu ’) and DC-stimulation/activation of antileukemic T-cells. Methods We analyzed, whether the addition of PINDs during DC cultures (15 healthy, 22 leukemic donors) and mixed lymphocyte culture (MLC, n = 15) with autologous (n = 6), allogeneic (n = 2) or T-cells after stem cell transplantation (SCT; n = 7) would alter the quality and quantity of DC, the composition of T-cell-subsets, and/or their antileukemic functionality (AF) as studied by FACS and functional Fluorolysis-cytotoxicity-assays. Results Effects on 1. DC-cultures: PINDs in DC-cultures lead to increased proportions of mature DC and DC leu , but reduced proportions of viable and overall, as well as TLR4- and TLR9-expressing DC. 2. MLC: PINDs increased early (CD8+) T-cell activation (CD69+), but reduced proportions of effector-T-cells after MLC 3. AF: Presence of PINDs in DC- and MLC-cultures reduced T-cells’ as well as innate cells’ antileukemic functionality. 4. Cytokine-release profile: Supernatants from PIND-treated DC- and MLC-cultures resembled an inhibitory microenvironment, correlating with impaired blast lysis. Conclusions Our data shows that addition of PINDs to DC-cultures and MLC result in a “blast-protective-capacity” leading to impaired AF, likely due to changes in the composition of T-/innate effector cells and the induction of an inhibitory microenvironment. PINDs might be promising in treating infectious diseases, but cannot be recommended for the treatment of AML-patients due to their inhibitory influence on antileukemic functionality. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
12. Programmable Nucleic Acid Nanoswitches for the Rapid, Single-Step Detection of Antibodies in Bodily Fluids.
- Author
-
Porchetta, Alessandro, Ippodrino, Rudy, Marini, Bruna, Caruso, Arnaldo, Caccuri, Francesca, and Ricci, Francesco
- Subjects
- *
IMMUNOGLOBULINS , *BODY fluids , *IMMUNIZATION , *ANTIGEN presentation , *SEROLOGY , *HIV infections -- Immunological aspects , *HIV infections , *THERAPEUTICS , *AIDS vaccines , *PHYSIOLOGY - Abstract
Antibody detection plays a pivotal role in the diagnosis of pathogens and monitoring the success of vaccine immunization. However, current serology techniques require multiple, time-consuming washing and incubation steps, which limit their applicability in point-of-care (POC) diagnostics and high-throughput assays. We developed here a nucleic acid nanoswitch platform able to instantaneously measure immunoglobulins of type G and E (IgG and IgE) levels directly in blood serum and other bodily fluids. The system couples the advantages of targetbinding induced colocalization and nucleic acid conformational-change nanoswitches. Due to the modular nature of the recognition platform, the method can potentially be applied to the detection of any antibody for which an antigen can be conjugated to a nucleic acid strand. In this work we show the sensitive, fast and cost-effective detection of four different antibodies and demonstrate the possible use of this approach for the monitoring of antibody levels in HIV+ patients immunized with AT20 therapeutic vaccine. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
13. Crystal structures of H-2Db in complex with the LCMV-derived peptides GP92 and GP392 explain pleiotropic effects of glycosylation on antigen presentation and immunogenicity.
- Author
-
Hafstrand, Ida, Badia-Martinez, Daniel, Josey, Benjamin John, Norström, Melissa, Buratto, Jérémie, Pellegrino, Sara, Duru, Adil Doganay, Sandalova, Tatyana, and Achour, Adnane
- Subjects
- *
GLYCOSYLATION , *CRYSTAL structure , *IMMUNE recognition , *ANTIGEN presentation , *POST-translational modification , *MAJOR histocompatibility complex , *EPITOPES - Abstract
Post-translational modifications significantly broaden the epitope repertoire for major histocompatibility class I complexes (MHC-I) and may allow viruses to escape immune recognition. Lymphocytic choriomeningitis virus (LCMV) infection of H-2b mice generates CD8+ CTL responses directed towards several MHC-I-restricted epitopes including the peptides GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL), both with a N-glycosylation site. Interestingly, glycosylation has different effects on the immunogenicity and association capacity of these two epitopes to H-2Db. To assess the structural bases underlying these functional results, we determined the crystal structures of H-2Db in complex with GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL) to 2.4 and 2.5 Å resolution, respectively. The structures reveal that while glycosylation of GP392 most probably impairs binding, the glycosylation of the asparagine residue in GP92, which protrudes towards the solvent, possibly allows for immune escape and/or forms a neo-epitope that may select for a different set of CD8 T cells. Altogether, the presented results provide a structural platform underlying the effects of post-translational modifications on epitope binding and/or immunogenicity, resulting in viral immune escape. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
14. Mycobacterium tuberculosis Modulates miR-106b-5p to Control Cathepsin S Expression Resulting in Higher Pathogen Survival and Poor T-Cell Activation.
- Author
-
Pires, David, Bernard, Elliott M., Pombo, João Palma, Carmo, Nuno, Fialho, Catarina, Gutierrez, Maximiliano Gabriel, Bettencourt, Paulo, and Anes, Elsa
- Subjects
MYCOBACTERIUM tuberculosis ,MICRORNA ,CATHEPSINS ,HOSTS (Biology) ,MACROPHAGES ,T cells ,PHYSIOLOGY - Abstract
The success of tuberculosis (TB) bacillus, Mycobacterium tuberculosis (Mtb), relies on the ability to survive in host cells and escape to immune surveillance and activation. We recently demonstrated that Mtb manipulation of host lysosomal cathepsins in macrophages leads to decreased enzymatic activity and pathogen survival. In addition, while searching for microRNAs (miRNAs) involved in posttranscriptional gene regulation during mycobacteria infection of human macrophages, we found that selected miRNAs such as miR-106b-5p were specifically upregulated by pathogenic mycobacteria. Here, we show that miR-106b-5p is actively manipulated by Mtb to ensure its survival in macrophages. Using an in silico prediction approach, we identified miR-106b-5p with a potential binding to the 3'-untranslated region of cathepsin S (CtsS) mRNA. We demonstrated by luminescence-based methods that miR-106b-5p indeed targets CTSS mRNA resulting in protein translation silencing. Moreover, miR-106b-5p gain-offunction experiments lead to a decreased CtsS expression favoring Mtb intracellular survival. By contrast, miR-106b-5p loss-of-function in infected cells was concomitant with increased CtsS expression, with significant intracellular killing of Mtb and T-cell activation. Modulation of miR-106b-5p did not impact necrosis, apoptosis or autophagy arguing that miR-106b-5p directly targeted CtsS expression as a way for Mtb to avoid exposure to degradative enzymes in the endocytic pathway. Altogether, our data suggest that manipulation of miR-106b-5p as a potential target for host-directed therapy for Mtb infection. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
15. IFN-γ alters the expression of diverse immunity related genes in a cell culture model designed to represent maturing neutrophils.
- Author
-
Ellison, Michael A., Gearheart, Christy M., Porter, Christopher C., and Ambruso, Daniel R.
- Subjects
- *
CHRONIC granulomatous disease treatment , *THERAPEUTIC use of interferons , *NEUTROPHILS , *CELL culture , *MAJOR histocompatibility complex , *CHEMOKINES - Abstract
The cytokine interferon-γ (IFN-γ) is approved as a drug to treat chronic granulomatous disease (CGD) and osteopetrosis and is also used in hyperimmunoglobulin E syndromes. Patients with CGD have defects in proteins of the NOX2 NADPH oxidase system. This leads to reduced production of microbicidal ROS by PMNs and recurrent life threatening infections. The goal of this study was to better understand how IFN-γ might support phagocyte function in these diseases, and to obtain information that might expand potential uses for IFN-γ. Neutrophils mature in the bone marrow and then enter the blood where they quickly undergo apoptotic cell death with a half-life of only 5–10 hours. Therefore we reasoned that IFN-γ might exert its effects on neutrophils via prolonged exposure to cells undergoing maturation in the marrow rather than by its brief exposure to short-lived circulating cells. To explore this possibility we made use of PLB-985 cells, a myeloblast-like myeloid cell line that can be differentiated into a mature, neutrophil-like state by treatment with various agents including DMSO. In initial studies we investigated transcription and protein expression in PLB-985 cells undergoing maturation in the presence or absence of IFN-γ. We observed IFN-γ induced differences in expression of genes known to be involved in classical aspects of neutrophil function (transmigration, chemotaxis, phagocytosis, killing and pattern recognition) as well as genes involved in apoptosis and other mechanisms that regulating neutrophil number. We also observed differences for genes involved in the major histocompatibility complex I (MHCI) and MHCII systems whose involvement in neutrophil function is controversial and not well defined. Finally, we observed significant changes in expression of genes encoding guanylate binding proteins (Gbps) that are known to have roles in immunity but which have not as yet been linked to neutrophil function. We propose that changes in the expression within these classes of genes could help explain the immune supportive effects of IFN-γ. Next we explored if the effect of IFN-γ on expression of these genes is dependent on whether the cells are undergoing maturation; to do this we compared the effects of IFN-γ on cells cultured with and without DMSO. For a subset of genes the expression level changes caused by IFN-γ were much greater in maturing cells than non-maturing cells. These findings indicate that developmental changes associated with cell maturation can modulate the effects of IFN-γ but that this is gene specific. Since the effects of IFN-γ depend on whether cells are maturing, the gene expression changes observed in this study must be due to more than just prolonged application of IFN-γ and are instead the result of interplay between cell maturation and changes caused by the chemokine. This supports our hypothesis that the effects of IFN-γ on developing neutrophils in the bone marrow may be very different from its effects on mature cells in the blood. Collectively the findings in this study enhance our understanding of the effects of IFN-γ on maturing myeloid cells and indicate possible mechanisms by which this cytokine could support immune function. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
16. Zerumbone modulates CD1d expression and lipid antigen presentation pathway in breast cancer cells.
- Author
-
Shyanti, Ritis K., Sehrawat, Anuradha, Singh, Shivendra V., Mishra, J.P.N., and Singh, Rana P.
- Subjects
- *
KILLER cells , *ANTIGEN presentation , *BREAST cancer treatment , *DOWNREGULATION , *GALACTOSYLCERAMIDES , *PHYSIOLOGY - Abstract
Natural Killer T (NKT) cells based cancer immunotherapy is an evolving area of cancer therapy, but tumors escape from this treatment modality by altering CD1d expression and its antigen presentation pathway. Here, we have studied the relation of CD1d expression in various breast cancer cell lines to their viability and progression. We observed a novel phenomenon that CD1d expression level increases with the progressive stage of the cancer. A small molecule, zerumbone (ZER) caused down-regulation of CD1d that was accompanied by breast cancer cell growth in vitro . The growth inhibitory effect of ZER against breast cancer cells was augmented by treatment with anti-CD1d mAb. This effect was mediated by G1-phase cell cycle arrest and apoptosis induction coupled with an increase in mitochondrial membrane depolarization. CD1d expression and cell proliferation were inhibited by both CD1d siRNA and ZER. The α-galactosylceramide, a ligand for CD1d, showed increased CD1d expression as well as cell proliferation which was opposite to the effects of ZER. This study shows that, CD1d overexpression is associated with the progressive stages of breast cancer and ZER could be an adjuvant to potentiate cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
17. Dysregulation of Rnf 213 gene contributes to T cell response via antigen uptake, processing, and presentation
- Author
-
Miki Fujimura, Shigeo Kure, Sherif Rashad, Teiji Tominaga, Ryosuke Tashiro, Jun Kasamatsu, Yuko Okuyama, Atsuo Kikuchi, Kuniyasu Niizuma, and Naoto Ishii
- Subjects
0301 basic medicine ,Physiology ,T-Lymphocytes ,Ubiquitin-Protein Ligases ,Clinical Biochemistry ,Antigen presentation ,Receptors, Antigen, T-Cell ,Biology ,Lymphocyte Activation ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Gene expression ,medicine ,Animals ,Antigens ,Antigen-presenting cell ,Cells, Cultured ,Cell Proliferation ,Adenosine Triphosphatases ,Mice, Knockout ,Antigen Presentation ,Mutation ,Antigen processing ,Dendritic Cells ,Cell Biology ,Dendritic cell ,Coculture Techniques ,Cell biology ,Ovalbumin ,Phenotype ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Moyamoya Disease - Abstract
Growing evidence suggest the association between Moyamoya disease (MMD) and immune systems, such as antigen presenting cells in particular. Rnf213 gene, a susceptibility gene for MMD, is highly expressed in immune tissues, however, its function remains unclear. In addition, the physiological role of RNF213 gene polymorphism c.14576G > A (rs112735431), susceptibility variant for MMD, is also poorly understood. By studying Rnf213-knockout (Rnf213-KO) mice with deletion of largest exon32 and Rnf213-knockin (Rnf213-KI) mice with insertion of single-nucleotide polymorphism corresponding to c.14576G > A mutation in MMD patients, we aimed to investigate the role of RNF213 in dendritic cell development, and antigen processing and presentation. First, we found a high level of Rnf213 gene expression in conventional DCs and monocytes. Second, flow cytometric and confocal microscopic analysis revealed ovalbumin protein-pulsed Rnf213-KO and Rnf213-KI DCs showed impaired antigen uptake, proteolysis and reduced numbers of endosomes and lysosomes, and thereby failed to activate and proliferate antigen-specific T cells efficiently. In addition, Rnf213-KI DCs showed a similar phenotype to that of Rnf213-KO BMDCs. In conclusion, our findings suggest the critical role of RNF213 in antigen uptake, processing and presentation.
- Published
- 2021
18. A Dual Promoter System to Monitor IFN-γ Signaling in vivo at Single-cell Resolution
- Author
-
Shinya Tsukiji, Michiyuki Matsuda, Kenta Terai, Hiroshi Ichise, Yoshinobu Konishi, and Taisei Tanaka
- Subjects
Tumor microenvironment ,Physiology ,Chemistry ,Antigen presentation ,Cell Biology ,General Medicine ,Immune checkpoint ,Cell biology ,Immune system ,In vivo ,Interferon ,Cancer cell ,medicine ,Interferon gamma ,Molecular Biology ,medicine.drug - Abstract
IFN-γ secreted from immune cells exerts pleiotropic effects on tumor cells, including induction of immune checkpoint and antigen presentation, growth inhibition, and apoptosis induction. We combined a dual promoter system with an IFN-γ signaling responsive promoter to generate a reporter named the interferon sensing probe (ISP), which quantitates the response to IFN-γ by means of fluorescence and bioluminescence. The integration site effect of the transgene is compensated for by the PGK promoter-driven expression of a fluorescent protein. Among five potential IFN-γ-responsive elements, we found that the interferon γ-activated sequence (GAS) exhibited the best performance. When ISP-GAS was introduced into four cell lines and subjected to IFN-γ stimulation, dose-dependency was observed with an EC50 ranging from 0.2 to 0.9 ng/mL, indicating that ISP-GAS can be generally used as a sensitive biosensor of IFN-γ response. In a syngeneic transplantation model, the ISP-GAS-expressing cancer cells exhibited bioluminescence and fluorescence signals in an IFN-γ receptor-dependent manner. Thus, ISP-GAS could be used to quantitatively monitor the IFN-γ response both in vitro and in vivo.Key words: in vivo imaging, tumor microenvironment, interferon-gamma, dual promoter system.
- Published
- 2021
19. High-dimensional single-cell analysis reveals the immune characteristics of COVID-19
- Author
-
Wenru Su, Pengjuan Ma, Jinguo Ye, Yingfeng Zheng, Hao Tang, Yizhi Liu, Wen Wen, Wen Shi, Qiqi Cao, Lihui Xie, Wenqing Le, and Xiuxing Liu
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Adult ,CD4-Positive T-Lymphocytes ,Male ,peripheral blood mononuclear cell ,Physiology ,Antigen presentation ,Plasma Cells ,Biology ,Plasma cell ,Peripheral blood mononuclear cell ,Lymphocyte Depletion ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Single-cell analysis ,Physiology (medical) ,medicine ,Humans ,Aged ,Antigen Presentation ,Innate immune system ,SARS-CoV-2 ,Monocyte ,COVID-19 ,acute phase ,convalescent phase ,Cell Biology ,Dendritic Cells ,Middle Aged ,medicine.disease ,Killer Cells, Natural ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Leukocytes, Mononuclear ,Cytokines ,Female ,CyTOF ,Single-Cell Analysis ,Cytokine storm ,Cytokine Release Syndrome ,Research Article - Abstract
Coronavirus disease 2019 (COVID-19), driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. Pathogenic T cells and inflammatory monocytes are regarded as the central drivers of the cytokine storm associated with the severity of COVID-19. In this study, we explored the characteristic peripheral cellular profiles of patients with COVID-19 in both acute and convalescent phases by single-cell mass cytometry (CyTOF). Using a combination of algorithm-guided data analyses, we identified peripheral immune cell subsets in COVID-19 and revealed CD4+ T-cell depletion, T-cell differentiation, plasma cell expansion, and the reduced antigen presentation capacity of innate immunity. Notably, COVID-19 induces a dysregulation in the balance of monocyte populations by the expansion of the monocyte subsets. Collectively, our results represent a high-dimensional, single-cell profile of the peripheral immune response to SARS-CoV-2 infection.
- Published
- 2020
20. Acetaldehyde suppresses HBV-MHC class I complex presentation on hepatocytes via induction of ER stress and Golgi fragmentation
- Author
-
Srivatsan Kidambi, Natalia A. Osna, Edward Makarov, Larisa Y. Poluektova, Murali Ganesan, Armen Petrosyan, Carol A. Casey, Saumi Mathews, and Kusum K. Kharbanda
- Subjects
0301 basic medicine ,Hepatitis B virus ,Physiology ,Gene Expression ,Golgi Apparatus ,Acetaldehyde ,Transfection ,medicine.disease_cause ,Major histocompatibility complex ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Physiology (medical) ,Eukaryotic initiation factor ,HLA-A2 Antigen ,MHC class I ,medicine ,Humans ,RNA, Messenger ,Antigen Presentation ,Hepatology ,biology ,Chemistry ,Endoplasmic reticulum ,Histocompatibility Antigens Class I ,Gastroenterology ,Hep G2 Cells ,Golgi apparatus ,Endoplasmic Reticulum Stress ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Liver ,Hepatocyte ,Unfolded Protein Response ,biology.protein ,Unfolded protein response ,symbols ,030211 gastroenterology & hepatology ,Research Article - Abstract
Alcohol consumption worsens hepatitis B virus (HBV) infection pathogenesis. We have recently reported that acetaldehyde suppressed HBV peptide-major histocompatibility complex I (MHC class I) complex display on hepatocytes, limiting recognition and subsequent removal of the infected hepatocytes by HBV-specific cytotoxic T lymphocytes (CTLs). This suppression was attributed to impaired processing of antigenic peptides by the proteasome. However, in addition to proteasome dysfunction, alcohol may induce endoplasmic reticulum (ER) stress and Golgi fragmentation in HBV-infected liver cells to reduce uploading of viral peptides to MHC class I and/or trafficking of this complex to the hepatocyte surface. Hence, the aim of this study was to elucidate whether alcohol-induced ER stress and Golgi fragmentation affect HBV peptide-MHC class I complex presentation on HBV+ hepatocytes. Here, we demonstrate that, while both acetaldehyde and HBV independently cause ER stress and Golgi fragmentation, the combined exposure provided an additive effect. Thus we observed an activation of the inositol-requiring enzyme 1α-X-box binding protein 1 and activation transcription factor (ATF)6α, but not the phospho PKR-like ER kinase-phospho eukaryotic initiation factor 2α-ATF4-C/EBP homologous protein arms of ER stress in HBV-transfected cells treated with acetaldehyde-generating system (AGS). In addition, Golgi proteins trans-Golgi network 46, GM130, and Giantin revealed punctate distribution, indicating Golgi fragmentation upon AGS exposure. Furthermore, the effects of acetaldehyde were reproduced by treatment with ER stress inducers, thapsigargin and tunicamycin, which also decreased the display of this complex and MHC class I turnover in HepG2.2.15 cells and HBV-infected primary human hepatocytes. Taken together, alcohol-induced ER stress and Golgi fragmentation contribute to the suppression of HBV peptide-MHC class I complex presentation on HBV+ hepatocytes, which may diminish their recognition by CTLs and promote persistence of HBV infection in hepatocytes. NEW & NOTEWORTHY Our current findings show that acetaldehyde accelerates endoplasmic reticulum (ER) stress by activating the unfolded protein response arms inositol-requiring enzyme 1α-X-box binding protein 1 and activation transcription factor (ATF)6α but not phospho PKR-like ER kinase-p eukaryotic initiation factor 2α-ATF4-C/EBP homologous protein in hepatitis B virus (HBV)-transfected HepG2.2.15 cells. It also potentiates Golgi fragmentation, as evident by punctate distribution of Golgi proteins, GM130, trans-Golgi network 46, and Giantin. While concomitantly increasing HBV DNA and HBV surface antigen titers, acetaldehyde-induced ER stress suppresses the presentation of HBV peptide-major histocompatibility complex I complexes on hepatocyte surfaces, thereby promoting the persistence of HBV infection in the liver.
- Published
- 2020
21. Interferon-γ treatment in vitro elicits some of the changes in cathepsin S and antigen presentation characteristic of lacrimal glands and corneas from the NOD mouse model of Sjögren’s Syndrome.
- Author
-
Meng, Zhen, Klinngam, Wannita, Edman, Maria C., and Hamm-Alvarez, Sarah F.
- Subjects
- *
INFLAMMATION , *AUTOIMMUNE disease treatment , *LACRIMAL apparatus , *MAJOR histocompatibility complex , *EPITHELIUM - Abstract
Inflammation and impaired secretion by lacrimal and salivary glands are hallmarks of the autoimmune disease, Sjögren’s Syndrome. These changes in the lacrimal gland promote dryness and inflammation of the ocular surface, causing pain, irritation and corneal damage. The changes that initiate and sustain autoimmune inflammation in the lacrimal gland are not well-established. Here we demonstrate that interferon-γ (IFN-γ) is significantly elevated in lacrimal gland and tears of the male NOD mouse, a model of autoimmune dacryoadenitis which exhibits many ocular characteristics of Sjögren’s Syndrome, by 12 weeks of age early in lacrimal gland inflammation. Working either with primary cultured lacrimal gland acinar cells from BALB/c mice and/or rabbits, in vitro IFN-γ treatment for 48 hr decreased expression of Rab3D concurrent with increased expression of cathepsin S. Although total cellular cathepsin S activity was not commensurately increased, IFN-γ treated lacrimal gland acinar cells showed a significant increase in carbachol-stimulated secretion of cathepsin S similar to the lacrimal gland in disease. In vitro IFN-γ treatment did not increase the expression of most components of major histocompatibility complex (MHC) class II-mediated antigen presentation although antigen presentation was slightly but significantly stimulated in primary cultured lacrimal gland acinar cells. However, exposure of cultured human corneal epithelial cells to IFN-γ more robustly increased expression and activity of cathepsin S in parallel with increased expression and function of MHC class II-mediated antigen presentation. We propose that early elevations in IFN-γ contribute to specific features of ocular disease pathology in Sjögren’s Syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
22. Molecular challenges imposed by MHC-I restricted long epitopes on T cell immunity.
- Author
-
Josephs, Tracy M., Grant, Emma J., and Gras, Stephanie
- Subjects
- *
MAJOR histocompatibility complex , *T cells , *CD8 antigen , *EPITOPES , *MOLECULAR recognition , *PHYSIOLOGY - Abstract
It has widely been accepted that major histocompatibility complex class I molecules (MHC-I) are limited to binding small peptides of 8-10 residues in length. However, this consensus has recently been challenged with the identification of longer peptides (= 11 residues) that can also elicit cytotoxic CD8 + T cell responses. Indeed, a growing number of studies demonstrate that these noncanonical epitopes are important targets for the immune system. As long epitopes represent up to 10% of the peptide repertoire bound to MHC-I molecules, here we review their impact on antigen presentation by MHC-I, TCR recognition, and T cell immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
23. The MHC class II antigen presentation pathway in human monocytes differs by subset and is regulated by cytokines.
- Author
-
Lee, Justin, Tam, Hanson, Adler, Lital, Ilstad-Minnihan, Alexandra, Macaubas, Claudia, and Mellins, Elizabeth D.
- Subjects
- *
MAJOR histocompatibility complex , *ANTIGEN presentation , *MONOCYTES , *CYTOKINES , *INTERLEUKIN-10 , *PHAGOCYTOSIS , *IMMUNE system - Abstract
Monocytes play a critical role in the innate and adaptive immune systems, performing phagocytosis, presenting antigen, and producing cytokines. They are a heterogeneous population that has been divided in humans into classical, intermediate, and non-classical subsets, but the roles of these subsets are incompletely understood. In this study, we investigated the expression patterns of MHC class II (MHCII) and associated molecules and find that the intermediate monocytes express the highest levels of the MHC molecules, HLA-DR (tested in n = 30 samples), HLA-DP (n = 30), and HLA-DQ (n = 10). HLA-DM (n = 30), which catalyzes the peptide exchange on the MHC molecules, is also expressed at the highest levels in intermediate monocytes. To measure HLA-DM function, we measured levels of MHCII-bound CLIP (class II invariant chain peptide, n = 23), which is exchanged for other peptides by HLA-DM. We calculated CLIP:MHCII ratios to normalize CLIP levels to MHCII levels, and found that intermediate monocytes have the lowest CLIP:MHCII ratio. We isolated the different monocyte subsets (in a total of 7 samples) and analyzed their responses to selected cytokines as model of monocyte activation: two M1-polarizing cytokines (IFNγ, GM-CSF), an M2-polarizing cytokine (IL-4) and IL-10. Classical monocytes exhibit the largest increases in class II pathway expression in response to stimulatory cytokines (IFNγ, GM-CSF, IL-4). All three subsets decrease HLA-DR levels after IL-10 exposure. Our findings argue that intermediate monocytes are the most efficient constitutive antigen presenting subset, that classical monocytes are recruited into an antigen presentation role during inflammatory responses and that IL-10 negatively regulates this function across all subsets. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
24. Dendritic cells that phagocytose apoptotic macrophages loaded with mycobacterial antigens activate CD8 T cells via cross-presentation.
- Author
-
Espinosa-Cueto, Patricia, Magallanes-Puebla, Alejandro, Castellanos, Carlos, and Mancilla, Raul
- Subjects
- *
IMMUNE response , *MYCOBACTERIUM tuberculosis , *DENDRITIC cells , *ALVEOLITIS , *LYMPH nodes - Abstract
While homeostatic apoptosis is immunologically silent, macrophage apoptosis during Mycobacterium tuberculosis infection can potentially induce an immune response against the mycobacteria. To examine the role of dendritic cells in this response, macrophage apoptosis was induced by incubating the macrophage with cell wall extracts of mycobacteria expressing LpqH. The apoptogenic proteins of the cell wall extracts were engulfed by the macrophage and then were translocated from the cytosol to the nuclei of the dying cells. Dendritic cells that engulfed the apoptotic macrophages acquired an immunogenic phenotype that included upregulation of MHC-I, increased expression of the costimulatory molecules, CD40, CD80, and CD86, and increased production of IL-12, IL-10, TNF-α, and TGF-β. In addition, the dendritic cells triggered a proliferative response of CD8+ T cells with IFN-γ production via cross-presentation. Taken together, these findings support a model in which phagocytosis of whole apoptotic cells carrying mycobacterial antigens promotes a potentially protective immune response. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
25. C1q as an autocrine and paracrine regulator of cellular functions.
- Author
-
Ghebrehiwet, Berhane, Hosszu, Kinga H., and Peerschke, Ellinor I.B.
- Subjects
- *
COMPLEMENT (Immunology) , *CELL metabolism , *AUTOCRINE mechanisms , *DENDRITIC cells , *ANTIGEN presentation , *SYSTEMIC lupus erythematosus , *IMMUNOLOGICAL tolerance , *PHYSIOLOGY , *IMMUNOLOGY - Abstract
Most of the complement proteins in circulation are, by and large, synthesized in the liver. However data accumulated over the past several decades provide incontrovertible evidence that some if not most of the individual complement proteins are also synthesized extrahepatically by activated as well as non-activated cells. The question that is finally being addressed by various investigators is: are the locally synthesized proteins solely responsible for the myriad of biological functions in situ without the contribution of systemic complement? The answer is probably “yes”. Among the proteins that are synthesized locally, C1q takes center stage for several reasons. First, it is synthesized predominantly by potent antigen presenting cells such as monocytes, macrophages and dendritic cells (DCs), which by itself is a clue that it plays an important role in antigen presentation and/or DC maturation. Second, it is transiently anchored on the cell surface via a transmembrane domain located in its A chain before it is cleaved off and released into the pericellular milieu. The membrane-associated C1q in turn, is able to sense danger patterns via its versatile antigen-capturing globular head domains. More importantly, locally synthesized C1q has been shown to induce a plethora of biological functions through the induction of immunomodulatory molecules by an autocrine- or paracrine- mediated signaling in a manner that mimics those of TNFα. These include recognition of pathogen- and danger- associated molecular patterns, phagocytosis, angiogenesis, apoptosis and induction of cytokines or chemokines that are important in modulating the inflammatory response. The functional convergence between C1q and TNFα in turn is attributed to their shared genetic ancestry. In this paper, we will infer to the aforementioned “local-synthesis-for-local function” paradigm using as an example, the role played by locally synthesized C1q in autoimmunity in general and in systemic lupus erythematosus in particular. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
26. Heterogeneity, functional specialization and differentiation of monocyte-derived dendritic cells.
- Author
-
Chow, Kevin V, Sutherland, Robyn M, Zhan, Yifan, and Lew, Andrew M
- Subjects
- *
MONOCYTES , *DENDRITIC cell anatomy , *IMMUNOREGULATION , *HETEROGENEITY , *ANTIGEN presentation , *AUTOIMMUNITY , *PHYSIOLOGY - Abstract
Dendritic cells (DCs) are professional antigen-presenting cells that consist of functionally and phenotypically heterogeneous populations. Monocyte-derived DCs (moDCs) are a DC subset that have been attracting increasing interest owing to their potent influence on adaptive immune function and their rapid accumulation upon an inflammatory stimulus. Although early studies on moDCs mainly addressed infection, their emergence and function in other settings such as autoimmunity and allogeneic organ transplantation are now being increasingly appreciated. In this review, the relationship between murine monocyte subsets and the moDCs that arise from them is discussed. Their role in initiating and modulating innate and adaptive immune responses in various pathophysiological scenarios is also explored, including how they may separate their labour from conventional DCs. How these findings might relate to their human counterparts is also discussed. Overall, monocytes and moDCs exhibit complex and heterogeneous behaviours that are critical in responses against microbial invasion, autoimmunity and allograft rejection. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
27. Pulmonary persistence of graphene nanoplatelets may disturb physiological and immunological homeostasis.
- Author
-
Park, Eun‐Jung, Lee, Sang Jin, Lee, Kyuhong, Choi, Young Chul, Lee, Byoung‐Seok, Lee, Gwang‐Hee, and Kim, Dong‐Wan
- Subjects
HOMEOSTASIS ,GRAPHENE synthesis ,IMMUNOTOXICOLOGY ,PHYSIOLOGY ,ANTIGEN presentation ,POLYCYCLIC aromatic hydrocarbons - Abstract
Accumulated evidence suggests that chronic pulmonary accumulation of harmful particles cause adverse pulmonary and systemic health effects. In our previous study, most of the graphene nanoplatelet (GNP) remained in the lung until 28 days after a single instillation. In this study, we sought to evaluate the local and systemic health effect after a long pulmonary persistence of GNP. As expected, GNP remained in the lung on day 90 after a single intratracheal instillation (1.25, 2.5 and 5 mg kg
−1 ). In the lung exposed at the highest dose, the total number of cells and the percentage of lymphocytes significantly increased in the BAL fluid with an increase in both the number of GNP-engulfed macrophages and the percentage of apoptotic cells. A Th1-shifted immune response, the elevated chemokine secretion and the enhanced expression of cytoskeletal-related genes were observed. Additionally, the expression of natriuretic-related genes was noteworthy altered in the lungs. Moreover, the number of white blood cells (WBC) and the percentage of macrophages and neutrophils clearly increased in the blood of mice exposed to a 5-mg kg−1 dose, whereas total protein, BUN and potassium levels significantly decreased. In conclusion, we suggest that the long persistence of GNP in the lung may cause adverse health effects by disturbing immunological- and physiological-homeostasis of our body. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
28. Multi-layered control of Galectin-8 mediated autophagy during adenovirus cell entry through a conserved PPxY motif in the viral capsid.
- Author
-
Montespan, Charlotte, Marvin, Shauna A., Austin, Sisley, Burrage, Andrew M., Roger, Benoit, Rayne, Fabienne, Faure, Muriel, Campell, Edward M., Schneider, Carola, Reimer, Rudolph, Grünewald, Kay, Wiethoff, Christopher M., and Wodrich, Harald
- Subjects
- *
AUTOPHAGY , *ADENOVIRUSES , *PATHOGENIC microorganisms , *LYSOSOMES , *ENDOSOMES - Abstract
Cells employ active measures to restrict infection by pathogens, even prior to responses from the innate and humoral immune defenses. In this context selective autophagy is activated upon pathogen induced membrane rupture to sequester and deliver membrane fragments and their pathogen contents for lysosomal degradation. Adenoviruses, which breach the endosome upon entry, escape this fate by penetrating into the cytosol prior to autophagosome sequestration of the ruptured endosome. We show that virus induced membrane damage is recognized through Galectin-8 and sequesters the autophagy receptors NDP52 and p62. We further show that a conserved PPxY motif in the viral membrane lytic protein VI is critical for efficient viral evasion of autophagic sequestration after endosomal lysis. Comparing the wildtype with a PPxY-mutant virus we show that depletion of Galectin-8 or suppression of autophagy in ATG5-/- MEFs rescues infectivity of the PPxY-mutant virus while depletion of the autophagy receptors NDP52, p62 has only minor effects. Furthermore we show that wildtype viruses exploit the autophagic machinery for efficient nuclear genome delivery and control autophagosome formation via the cellular ubiquitin ligase Nedd4.2 resulting in reduced antigenic presentation. Our data thus demonstrate that a short PPxY-peptide motif in the adenoviral capsid permits multi-layered viral control of autophagic processes during entry. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
29. B Cell Immunity in Solid Organ Transplantation.
- Author
-
Karahan, Gonca E., Claas, Frans H. J., Heidt, Sebastiaan, Tambur, Anat R., and Duquesnoy, Rene
- Subjects
B cells ,CELLULAR immunity ,TRANSPLANTATION of organs, tissues, etc. ,PHYSIOLOGY - Abstract
The contribution of B cells to alloimmune responses is gradually being understood in more detail. We now know that B cells can perpetuate alloimmune responses in multiple ways: (i) differentiation into antibody-producing plasma cells; (ii) sustaining long-term humoral immune memory; (iii) serving as antigen-presenting cells; (iv) organizing the formation of tertiary lymphoid organs; and (v) secreting pro- as well as anti-inflammatory cytokines. The cross-talk between B cells and T cells in the course of immune responses forms the basis of these diverse functions. In the setting of organ transplantation, focus has gradually shifted from T cells to B cells, with an increased notion that B cells are more than mere precursors of antibody-producing plasma cells. In this review, we discuss the various roles of B cells in the generation of alloimmune responses beyond antibody production, as well as possibilities to specifically interfere with B cell activation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
30. PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity.
- Author
-
Wiede, Florian, Sacirbegovic, Faruk, Leong, Yew Ann, Yu, Di, and Tiganis, Tony
- Subjects
- *
AUTOIMMUNITY , *T helper cells , *B cells , *SINGLE nucleotide polymorphisms , *ANTIGEN presentation , *PHYSIOLOGY - Abstract
Non-coding single nucleotide polymorphisms that repress PTPN2 expression have been linked with the development of type 1 diabetes, rheumatoid arthritis and Crohn's disease. PTPN2 attenuates CD8 + T cell responses to self and prevents overt autoreactivity in the context of T cell homeostasis and antigen cross-presentation. The role of PTPN2 in other immune subsets in the development of autoimmunity remains unclear. Here we show that the inducible deletion of PTPN2 in hematopoietic compartment of adult non-autoimmune prone mice results in systemic inflammation and autoimmunity. PTPN2-deficient mice had increased inflammatory monocytes, B cells and effector T cells in lymphoid and non-lymphoid tissues and exhibited symptoms of dermatitis, glomerulonephritis, pancreatitis and overt liver disease. Autoimmunity was characterised by the formation of germinal centers in the spleen and associated with markedly increased germinal center B cells and T follicular helper (T fh ) cells and circulating anti-nuclear antibodies, inflammatory cytokines and immunoglobulins. CD8 + T cell proliferative responses were enhanced, and interleukin-21-induced STAT-3 signalling in T fh cells and B cells was increased and accompanied by enhanced B cell proliferation ex vivo . These results indicate that deficiencies in PTPN2 across multiple immune lineages, including naive T cells, T fh cells and B cells, contribute to the development of autoimmunity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
31. Dendritic cells tip the balance towards induction of regulatory T cells upon priming in experimental autoimmune encephalomyelitis.
- Author
-
Paterka, Magdalena, Voss, Jan Oliver, Werr, Johannes, Reuter, Eva, Franck, Sophia, Leuenberger, Tina, Herz, Josephine, Radbruch, Helena, Bopp, Tobias, Siffrin, Volker, and Zipp, Frauke
- Subjects
- *
IMMUNOLOGICAL aspects of encephalomyelitis , *DENDRITIC cells , *ANTIGEN presentation , *IMMUNOREGULATION , *T cells , *PHYSIOLOGY - Abstract
Counter-balancing regulatory mechanisms, such as the induction of regulatory T cells (Treg), limit the effects of autoimmune attack in neuroinflammation. However, the role of dendritic cells (DCs) as the most powerful antigen-presenting cells, which are intriguing therapeutic targets in this context, is not fully understood. Here, we demonstrate that conditional ablation of DCs during the priming phase of myelin-specific T cells in experimental autoimmune encephalomyelitis (EAE) selectively aborts inducible Treg (iTreg) induction, whereas generation of T helper (Th)1/17 cells is unaltered. DCs facilitate iTreg induction by creating a milieu with high levels of interleukin (IL)-2 due to a strong proliferative response. In the absence of DCs, B220 + B cells take over priming of Th17 cells in the place of antigen-presenting cells (APCs), but not the induction of iTreg, thus leading to unregulated, severe autoimmunity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
32. Antigen presentation for priming T cells in central system.
- Author
-
Dasgupta, Shaoni and Dasgupta, Subhajit
- Subjects
- *
ANTIGEN presentation , *NEUROIMMUNOLOGY , *T cells , *DEMYELINATION , *IMMUNOTHERAPY , *PHYSIOLOGY - Abstract
Generation of myelin antigen-specific T cells is a major event in neuroimmune responses that causes demyelination. The antigen-priming of T cells and its location is important in chronic and acute inflammation. In autoimmune multiple sclerosis, the effector T cells are considered to generate in periphery. However, the reasons for chronic relapsing-remitting events are obscure. Considering mechanisms, a feasible aim of research is to investigate the role of antigen-primed T cells in lupus cerebritis. Last thirty years of investigations emphasize the relevance of microglia and infiltrated dendritic cells/macrophages as antigen presenting cells in the central nervous system. The recent approach towards circulating B-lymphocytes is an important area in the context. Here, we analyze the existing findings on antigen presentation in the central nervous system. The aim is to visualize signaling events of myelin antigen presentation to T cells and lead to the strategy of future goals on immunotherapy research. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
33. Liver Monocytes and Kupffer Cells Remain Transcriptionally Distinct during Chronic Viral Infection.
- Author
-
van de Garde, Martijn D. B., Movita, Dowty, van der Heide, Marieke, Herschke, Florence, De Jonghe, Sandra, Gama, Lucio, Boonstra, Andre, and Vanwolleghem, Thomas
- Subjects
- *
ANIMAL models for virus diseases , *MONOCYTES , *LIVER cells , *KUPFFER cells , *GENETIC transcription , *IMMUNOCOMPETENT cells , *VIRAL replication - Abstract
Due to the scarcity of immunocompetent animal models for chronic viral hepatitis, little is known about the role of the innate intrahepatic immune system during viral replication in the liver. These insights are however fundamental for the understanding of the inappropriate adaptive immune responses during the chronic phase of the infection. We apply the Lymphocytic Choriomenigitis Virus (LCMV) clone 13 mouse model to examine chronic virus-host interactions of Kupffer cells (KC) and infiltrating monocytes (IM) in an infected liver. LCMV infection induced overt clinical hepatitis, with rise in ALT and serum cytokines, and increased intrahepatic F4/80 expression. Despite ongoing viral replication, whole liver transcriptome showed baseline expression levels of inflammatory cytokines, interferons, and interferon induced genes during the chronic infection phase. Transcriptome analyses of sorted KC and IMs using NanoString technology revealed two unique phenotypes with only minimal overlap. At the chronic viral infection phase, KC showed no increased transcription of activation markers Cd80 and Cd86, but an increased expression of genes related to antigen presentation, whereas monocytes were more activated and expressed higher levels of Tnf transcripts. Although both KCs and intrahepatic IM share the surface markers F4/80 and CD11b, their transcriptomes point towards distinctive roles during virus-induced chronic hepatitis. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
34. COVID-19 and the Immune System
- Author
-
Daniel Smrz, J Paces, Zuzana Strizova, and J Cerny
- Subjects
0301 basic medicine ,COVID-19 Vaccines ,Physiology ,Pneumonia, Viral ,Antigen presentation ,Inflammation ,Adaptive Immunity ,Biology ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Hot Topic Review ,Immunity ,medicine ,Humans ,Cytotoxic T cell ,Pandemics ,Innate immune system ,SARS-CoV-2 ,COVID-19 ,Viral Vaccines ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Acquired immune system ,Immunity, Innate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Immunology ,biology.protein ,Antibody ,medicine.symptom ,Coronavirus Infections - Abstract
A close interaction between the virus SARS-CoV-2 and the immune system of an individual results in a diverse clinical manifestation of the COVID-19 disease. While adaptive immune responses are essential for SARS-CoV-2 virus clearance, the innate immune cells, such as macrophages, may contribute, in some cases, to the disease progression. Macrophages have shown a significant production of IL-6, suggesting they may contribute to the excessive inflammation in COVID-19 disease. Macrophage Activation Syndrome may further explain the high serum levels of CRP, which are normally lacking in viral infections. In adaptive immune responses, it has been revealed that cytotoxic CD8+ T cells exhibit functional exhaustion patterns, such as the expression of NKG2A, PD-1, and TIM-3. Since SARS-CoV-2 restrains antigen presentation by downregulating MHC class I and II molecules and, therefore, inhibits the T cell-mediated immune responses, humoral immune responses also play a substantial role. Specific IgA response appears to be stronger and more persistent than the IgM response. Moreover, IgM and IgG antibodies show similar dynamics in COVID-19 disease.
- Published
- 2020
35. Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance
- Author
-
Annette Paschen and Beatrice Thier
- Subjects
tumor ,Cancer Research ,Physiology ,T cell ,t cell resistance ,Antigen presentation ,Medizin ,lcsh:Medicine ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Immune system ,Interferon ,Medicine ,Cytotoxic T cell ,hla class i ,lcsh:QH301-705.5 ,business.industry ,Antigen processing ,rig-i ,lcsh:R ,interferon ,immune checkpoint blockade ,Immune checkpoint ,medicine.anatomical_structure ,lcsh:Biology (General) ,Cancer research ,Molecular Medicine ,business ,CD8 ,medicine.drug - Abstract
In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in ICB, besides HLA-I APM suppression. Seeking for a strategy to overcome these barriers, we identified a novel mechanism that restores HLA-I antigen presentation in tumor cells independent of IFN (Such et al. (2020) J Clin Invest, doi: 10.1172/JCI131572). We demonstrated that tumor cell-intrinsic activation of the cytosolic innate immunoreceptor RIG-I by its synthetic ligand 3pRNA overcomes transcriptional HLA-I APM suppression in patient-derived IFN-resistant melanoma cells. De novo HLA-I APM expression is IRF1/IRF3-dependent and re-sensitizes melanoma cells to autologous cytotoxic CD8+ T cells. Notably, synthetic RIG-I ligands and ICB synergize in T cell activation, suggesting combinational therapy could be an efficient strategy to improve patient outcomes in melanoma.
- Published
- 2021
36. Leveraging Immunopeptidomics To Study and Combat Infectious Disease
- Author
-
Owen K Leddy, Forest M. White, and Bryan D. Bryson
- Subjects
0301 basic medicine ,animal structures ,Physiology ,infectious disease ,T cell ,Antigen presentation ,Priming (immunology) ,Context (language use) ,Biochemistry ,Microbiology ,immunology ,03 medical and health sciences ,proteomics ,0302 clinical medicine ,Immune system ,Antigen ,Genetics ,medicine ,Global health ,host-pathogen interactions ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,mass spectrometry ,business.industry ,immunopeptidomics ,vaccines ,QR1-502 ,Computer Science Applications ,030104 developmental biology ,medicine.anatomical_structure ,Infectious disease (medical specialty) ,Modeling and Simulation ,Immunology ,Minireview ,business ,030217 neurology & neurosurgery - Abstract
T cells must recognize pathogen-derived peptides bound to major histocompatibility complexes (MHCs) in order to initiate a cell-mediated immune response against an infection, or to support the development of high-affinity antibody responses. Identifying antigens presented on MHCs by infected cells and professional antigen-presenting cells (APCs) during infection may therefore provide a route toward developing new vaccines. Peptides bound to MHCs can be identified at whole-proteome scale using mass spectrometry—a technique referred to as “immunopeptidomics.” This technique has emerged as a powerful tool for identifying potential vaccine targets in the context of many infectious diseases. In this review, we discuss the contributions immunopeptidomic studies have made to understanding antigen presentation and T cell priming in the context of infection and the potential for immunopeptidomics to inform the development of vaccines to address pressing global health problems in infectious disease.
- Published
- 2021
37. A humanized monoclonal antibody against the endothelial chemokine CCL21 for the diagnosis and treatment of inflammatory bowel disease
- Author
-
Hal E. Broxmeyer, Elizabeth A. Williamson, Sarah C. Glover, Austin Kirby, Yilianys Pride, Maegan L. Capitano, Aruna S. Jaiswal, Gayathri Srinivasan, Daniel D Mais, Robert Hromas, and Fatemah G. Amlashi
- Subjects
0301 basic medicine ,Chemokine ,Physiology ,C-C chemokine receptor type 7 ,Inflammatory bowel disease ,Biochemistry ,White Blood Cells ,Mice ,0302 clinical medicine ,Venules ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Mice, Inbred BALB C ,Multidisciplinary ,Immune System Proteins ,biology ,T Cells ,Chemotaxis ,T-Lymphocytes, Helper-Inducer ,Cell Motility ,030220 oncology & carcinogenesis ,Medicine ,Antibody ,Cellular Types ,Anatomy ,Chemokines ,Venule Endothelium ,Research Article ,Protein Binding ,endocrine system ,Receptors, CCR7 ,medicine.drug_class ,Science ,Immune Cells ,Antigen presentation ,Immunology ,Gastroenterology and Hepatology ,Monoclonal antibody ,Research and Analysis Methods ,Antibodies, Monoclonal, Humanized ,Antibodies ,03 medical and health sciences ,medicine ,Animals ,Humans ,Endothelium ,Molecular Biology Techniques ,Molecular Biology ,Blood Cells ,Chemokine CCL21 ,business.industry ,Inflammatory Bowel Disease ,Biology and Life Sciences ,Proteins ,Cell Biology ,medicine.disease ,Inflammatory Bowel Diseases ,Monoclonal Antibodies ,030104 developmental biology ,biology.protein ,Cardiovascular Anatomy ,Blood Vessels ,business ,CCL21 ,Cloning - Abstract
Chemokines are small proteins that promote leukocyte migration during development, infection, and inflammation. We and others isolated the unique chemokine CCL21, a potent chemo-attractant for naïve T-cells, naïve B-cells, and immature dendritic cells. CCL21 has a 37 amino acid carboxy terminal extension that is distinct from the rest of the chemokine family, which is thought to anchor it to venule endothelium where the amino terminus can interact with its cognate receptor, CCR7. We and others have reported that venule endothelium expressing CCL21 plays a crucial role in attracting naïve immune cells to sites of antigen presentation. In this study we generated a series of monoclonal antibodies to the amino terminus of CCL21 in an attempt to generate an antibody that blocked the interaction of CCL21 with its receptor CCR7. We found one humanized clone that blocked naïve T-cell migration towards CCL21, while memory effector T-cells were less affected. Using this monoclonal antibody, we also demonstrated that CCL21 is expressed in the mucosal venule endothelium of the large majority of inflammatory bowel diseases (IBD), including Crohn’s disease, ulcerative colitis, and also in celiac disease. This expression correlated with active IBD in 5 of 6 cases, whereas none of 6 normal bowel biopsies had CCL21 expression. This study raises the possibility that this monoclonal antibody could be used to diagnose initial or recurrent of IBD. Significantly, this antibody could also be used for therapeutic intervention in IBD by selectively interfering with recruitment of naïve immune effector cells to sites of antigen presentation, without harming overall memory immunity.
- Published
- 2021
38. Macropinocytosis in Phagocytes: Regulation of MHC Class-II-Restricted Antigen Presentation in Dendritic Cells
- Author
-
Zhenzhen eLiu and Paul A. Roche
- Subjects
Antigen Presentation ,Endocytosis ,dendritic cell ,MHC class II ,macropinocytosis ,Physiology ,QP1-981 - Abstract
AbstractDendritic cells (DCs) are outstanding antigen presenting cells (APCs) due to their robust ability to internalize extracellular antigens using endocytic processes such as receptor-mediated endocytosis, phagocytosis, and macropinocytosis. Macropinocytosis mediates the non-specific uptake of soluble antigens and occurs in DCs constitutively. Macropinocytosis plays a key role in DC-mediated antigen presentation to T cells against pathogens and the efficiency of macropinocytosis in antigen capture is regulated during the process of DC maturation. Here, we review the methods to study macropinocytosis, describe our current knowledge of the regulatory mechanisms of antigen uptake via macropinocytosis and the intracellular trafficking route followed by macropinocytosed antigens, and discuss the significance of macropinocytosis for DC function.
- Published
- 2015
- Full Text
- View/download PDF
39. Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4.
- Author
-
Schuette, Verena, Embgenbroich, Maria, Ulas, Thomas, Welz, Meike, Schulte-Schrepping, Jonas, Draffehn, Astrid M., Quast, Thomas, Koch, Katharina, Nehring, Melanie, König, Jessica, Zweynert, Annegret, Harms, Frederike L., Steiner, Nancy, Limmer, Andreas, Förster, Irmgard, Berberich-Siebelt, Friederike, Knolle, Percy A., Wohlleber, Dirk, Kolanus, Waldemar, and Beyer, Marc
- Subjects
- *
MANNOSE , *T cells , *CD45 antigen , *ANTIGEN presentation , *CYTOTOXIC T lymphocyte-associated molecule-4 , *CELLULAR control mechanisms , *PHYSIOLOGY - Abstract
The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8+ T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
40. The Value of Online Algorithms to Predict T-Cell Ligands Created by Genetic Variants.
- Author
-
van der Lee, Dyantha I., Pont, Margot J., Falkenburg, J. H. Frederik, and Griffioen, Marieke
- Subjects
- *
T cells , *ONLINE algorithms , *STEM cell transplantation , *MINOR histocompatibility antigens , *IMMUNE response , *IN vivo studies - Abstract
Allogeneic stem cell transplantation can be a curative treatment for hematological malignancies. After HLA-matched allogeneic stem cell transplantation, beneficial anti-tumor immunity as well as detrimental side-effects can develop due to donor-derived T-cells recognizing polymorphic peptides that are presented by HLA on patient cells. Polymorphic peptides on patient cells that are recognized by specific T-cells are called minor histocompatibility antigens (MiHA), while the respective peptides in donor cells are allelic variants. MiHA can be identified by reverse strategies in which large sets of peptides are screened for T-cell recognition. In these strategies, selection of peptides by prediction algorithms may be relevant to increase the efficiency of MiHA discovery. We investigated the value of online prediction algorithms for MiHA discovery and determined the in silico characteristics of 68 autosomal HLA class I-restricted MiHA that have been identified as natural ligands by forward strategies in which T-cells from in vivo immune responses after allogeneic stem cell transplantation are used to identify the antigen. Our analysis showed that HLA class I binding was accurately predicted for 87% of MiHA of which a relatively large proportion of peptides had strong binding affinity (56%). Weak binding affinity was also predicted for a considerable number of antigens (31%) and the remaining 13% of MiHA were not predicted as HLA class I binding peptides. Besides prediction for HLA class I binding, none of the other online algorithms significantly contributed to MiHA characterization. Furthermore, we demonstrated that the majority of MiHA do not differ from their allelic variants in in silico characteristics, suggesting that allelic variants can potentially be processed and presented on the cell surface. In conclusion, our analyses revealed the in silico characteristics of 68 HLA class I-restricted MiHA and explored the value of online algorithms to predict T-cell ligands that are created by genetic variants. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
41. Maintenance of Mycobacterium tuberculosis-specific T cell responses in End Stage Renal Disease (ESRD) and implications for diagnostic efficacy.
- Author
-
Juno, Jennifer A., Waruk, Jillian L.M., Mesa, Christine, Lopez, Carmen, Bueti, Joe, Ball, T. Blake, and Kiazyk, Sandra A.
- Subjects
- *
MYCOBACTERIUM tuberculosis , *T cells , *DISEASE prevalence , *CHRONIC kidney failure , *INTERFERON gamma release tests , *ANTIGEN presentation , *DIAGNOSIS , *DISEASE risk factors , *PHYSIOLOGY - Abstract
End-stage renal disease (ESRD) patients exhibit elevated risk of tuberculosis (TB) reactivation, but current diagnostics, including the interferon gamma release assay (IGRA), exhibit poor sensitivity in ESRD. We tested 80 ESRD patients and found an 18.75% prevalence of IGRA positivity. A subset of patients was assessed for Mtb-specific expression of 44 cytokines/chemokines, and CD4 + T cell phenotype and function. Similar to non-ESRD IGRA + individuals, Mtb-specific IFNγ, IL-1RA, IP-10, MCP-3 and IL-2 responses were identified in the ESRD IGRA + group. 27% of the ESRD IGRA- group exhibited MCP-3 or IL-2 Mtb-specific responses, which may identify cases of latent TB infection in ESRD. Stimulation of PBMC with PPD demonstrated similar CD4 + T cell production of IFNγ, TNFα and GM-CSF by ESRD patients. The reported low sensitivity of the IGRA in ESRD cohorts is therefore unlikely to be due to poor T cell cytokine secretion, and may instead reflect defects in antigen presentation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
42. Defining cross presentation for a wider audience.
- Author
-
Norbury, Christopher C
- Subjects
- *
ANTIGEN presentation , *MAJOR histocompatibility complex , *CD8 antigen , *T cells , *IMMUNOGENETICS , *IMMUNE response , *ANTINEOPLASTIC agents , *PHYSIOLOGY - Abstract
Cross presentation is the process of production of peptide-MHC Class I complexes by cells in which the antigen that is the source of peptide is not translated. The majority of recent studies have described many facets of the classical TAP-dependent cross presentation pathway, but numerous pathways for transfer of antigenic material from a donor to a recipient cell followed by subsequent MHC-I-restricted presentation have been established, including transfer of protein antigen, peptide, RNA, DNA or even peptide-MHC-I complexes. The extent to which each of these pathways generates overlapping or unique peptide repertoires is unknown, as is the contribution of each of these pathways to generation of protective CD8+ T cells during infection or anti-tumor immune responses. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
43. Dendritic cell function and antigen presentation in malaria.
- Author
-
Cockburn, Ian A and Zavala, Fidel
- Subjects
- *
MALARIA immunology , *PLASMODIUM , *DENDRITIC cells , *ANTIGEN presentation , *T cells , *DISEASE progression , *CD8 antigen , *PHYSIOLOGY , *THERAPEUTICS - Abstract
Due to the diverse roles T cells play in protection against malaria as well as pathogenesis it is critical to know which cells present antigen and the nature of the antigens they present. During pre-erythrocytic stages of infection, cutting-edge imaging studies have shown how Plasmodium antigens are presented during both the priming and effector phases of the protective CD8+ T cell response. During blood stages, pathology is in part due to the loss of DC function and the action of pathogenic T cells in the brain. Recently endothelial cells presenting malaria antigen to cognate T cells have emerged as critical players in malaria pathogenesis. Manipulating these processes may inform both vaccine design and the development of therapies for cerebral malaria. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
44. Critical Role of Autophagy in the Processing of Adenovirus Capsid-Incorporated Cancer-Specific Antigens.
- Author
-
Klein, Sarah R., Jiang, Hong, Hossain, Mohammad B., Fan, Xuejun, Gumin, Joy, Dong, Andrew, Alonso, Marta M., Gomez-Manzano, Candelaria, and Fueyo, Juan
- Subjects
- *
ADENOVIRUSES , *CAPSIDS , *AUTOPHAGY , *IMMUNOTHERAPY , *CANCER cells , *VIRAL antigens - Abstract
Adenoviruses are highly immunogenic and are being examined as potential vectors for immunotherapy. Infection by oncolytic adenovirus is followed by massive autophagy in cancer cells. Here, we hypothesize that autophagy regulates the processing of adenoviral proteins for antigen presentation. To test this hypothesis, we first examined the presentation of viral antigens by infected cells using an antibody cocktail of viral capsid proteins. We found that viral antigens were processed by JNK-mediated autophagy, and that autophagy was required for their presentation. Consistent with these results, splenocytes isolated from virus-immunized mice were activated by infected cells in an MHC II-dependent manner. We then hypothesize that this mechanism can be utilized to generate an efficient cancer vaccine. To this end, we constructed an oncolytic virus encompassing an EGFRvIII cancer-specific epitope in the adenoviral fiber. Infection of cancer cells with this fiber-modified adenovirus resulted in recognition of infected cancer cells by a specific anti-EGFRvIII antibody. However, inhibition of autophagy drastically decreased the capability of the specific antibody to detect the cancer-related epitope in infected cells. Our data suggest that combination of adenoviruses with autophagy inducers may enhance the processing and presentation of cancer-specific antigens incorporated into capsid proteins. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
45. Analysis of the immune response of human dendritic cells to Mycobacterium tuberculosis by quantitative proteomics.
- Author
-
Chiu-Ping Kuo, Kuo-Song Chang, Jue-Liang Hsu, I-Fang Tsai, Andrew Boyd Lin, Tsai-Yin Wei, Chien-Liang Wu, and Yen-Ta Lu
- Subjects
- *
MYCOBACTERIUM tuberculosis , *IMMUNE response , *MEMBRANE proteins , *DENDRITIC cells , *FLOW cytometry , *PHYSIOLOGY - Abstract
Background: The cellular immune response for Mycobacterium tuberculosis (M. tuberculosis) infection remained incompletely understood. To uncover membrane proteins involved in this infection mechanism, an integrated approach consisting of an organic solvent-assisted membrane protein digestion, stable-isotope dimethyl labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to comparatively profile the membrane protein expression of human dendritic cells upon heat-killed M. tuberculosis (HKTB) treatment. Results: Organic solvent-assisted trypsin digestion coupled with stable-isotope labeling and LC-MS/MS analysis was applied to quantitatively analyze the membrane protein expression of THP-1 derived dendritic cells. We evaluated proteins that were upregulated in response to HKTB treatment, and applied STRING website database to analyze the correlations between these proteins. Of the investigated proteins, aminopeptidase N (CD13) was found to be largely expressed after HKTB treatment. By using confocal microscopy and flow cytometry, we found that membranous CD13 expression was upregulated and was capable of binding to live mycobacteria. Treatment dendritic cell with anti-CD13 antibody during M. tuberculosis infection enhanced the ability of T cell activation. Conclusions: Via proteomics data and STRING analysis, we demonstrated that the highly-expressed CD13 is also associated with proteins involved in the antigen presenting process, especially with CD1 proteins. Increasing expression of CD13 on dendritic cells while M. tuberculosis infection and enhancement of T cell activation after CD13 treated with anti-CD13 antibody indicates CD13 positively involved in the pathogenesis of M. tuberculosis. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
46. TAP-independent self-peptides enhance T cell recognition of immune-escaped tumors.
- Author
-
Doorduijn, Elien M., Sluijter, Marjolein, Querido, Bianca J., Oliveira, Cláudia C., Achour, Adnane, Ossendorp, Ferry, van der Burg, Sjoerd H., and van Hall, Thorbald
- Subjects
- *
T cells , *CD80 antigen , *IMMUNE response , *ANTIGEN presentation , *IMMUNOTHERAPY , *PHYSIOLOGY , *ANIMAL experimentation , *ANTIGENS , *CARRIER proteins , *CELL lines , *CELLULAR immunity , *HISTOCOMPATIBILITY antigens , *IMMUNITY , *MICE , *PEPTIDES , *TUMOR antigens , *TUMORS - Abstract
Tumor cells frequently escape from CD8+ T cell recognition by abrogating MHC-I antigen presentation. Deficiency in processing components, like the transporter associated with antigen processing (TAP), results in strongly decreased surface display of peptide/MHC-I complexes. We previously identified a class of hidden self-antigens known as T cell epitopes associated with impaired peptide processing (TEIPP), which emerge on tumor cells with such processing defects. In the present study, we analyzed thymus selection and peripheral behavior of T cells with specificity for the prototypic TEIPP antigen, the "self" TRH4 peptide/Db complex. TEIPP T cells were efficiently selected in the thymus, egressed with a naive phenotype, and could be exploited for immunotherapy against immune-escaped, TAP-deficient tumor cells expressing low levels of MHC-I (MHC-Ilo). In contrast, overt thymus deletion and functionally impaired TEIPP T cells were observed in mice deficient for TAP1 due to TEIPP antigen presentation on all body cells in these mice. Our results strongly support the concept that TEIPPs derive from ubiquitous, nonmutated self-antigens and constitute a class of immunogenic neoantigens that are unmasked during tumor immune evasion. These data suggest that TEIPP-specific CD8+ T cells are promising candidates in the treatment of tumors that have escaped from conventional immunotherapies. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
47. Immunological Characterization of Whole Tumour Lysate-Loaded Dendritic Cells for Cancer Immunotherapy.
- Author
-
Rainone, Veronica, Martelli, Cristina, Ottobrini, Luisa, Biasin, Mara, Borelli, Manuela, Lucignani, Giovanni, Trabattoni, Daria, and Clerici, Mario
- Subjects
- *
CANCER immunotherapy , *DENDRITIC cells , *CANCER cells , *T cells , *TUMOR antigens , *ANTINEOPLASTIC agents , *DRUG efficacy - Abstract
Introduction: Dendritic cells play a key role as initiators of T-cell responses, and even if tumour antigen-loaded dendritic cells can induce anti-tumour responses, their efficacy has been questioned, suggesting a need to enhance immunization strategies. Matherials & Methods: We focused on the characterization of bone marrow-derived dendritic cells pulsed with whole tumour lysate (TAA-DC), as a source of known and unknown antigens, in a mouse model of breast cancer (MMTV-Ras). Dendritic cells were evaluated for antigen uptake and for the expression of MHC class I/II and costimulatory molecules and markers associated with maturation. Results: Results showed that antigen-loaded dendritic cells are characterized by a phenotypically semi-mature/mature profile and by the upregulation of genes involved in antigen presentation and T-cell priming. Activated dendritic cells stimulated T-cell proliferation and induced the production of high concentrations of IL-12p70 and IFN-γ but only low levels of IL-10, indicating their ability to elicit a TH1-immune response. Furthermore, administration of Antigen loaded-Dendritic Cells in MMTV-Ras mice evoked a strong anti-tumour response in vivo as demonstrated by a general activation of immunocompetent cells and the release of TH1 cytokines. Conclusion: Data herein could be useful in the design of antitumoral DC-based therapies, showing a specific activation of immune system against breast cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
48. Human dendritic cell subsets and function in health and disease.
- Author
-
O'Keeffe, Meredith, Mok, Wai, and Radford, Kristen
- Subjects
- *
DENDRITIC cells , *ANTIGEN analysis , *AUTOIMMUNE diseases , *CELLULAR immunity , *INTERFERONS , *VIRUS diseases , *PHYSIOLOGY - Abstract
The method of choice for the development of new vaccines is to target distinct dendritic cell subsets with antigen in vivo and to harness their function in situ to enhance cell-mediated immunity or induce tolerance to specific antigens. The innate functions of dendritic cells themselves may also be targeted by inhibitors or activators that would target a specific function such as interferon production, potentially important in autoimmune disease and chronic viral infections. Importantly targeting dendritic cells requires detailed knowledge of both the surface phenotype and function of each dendritic cell subset, including how they may respond to different types of vaccine adjuvants, their ability to produce soluble mediators and to process and present antigens and induce priming of naïve T cells. This review summarizes our knowledge of the functional attributes of the human dendritic cell subsets in the steady state and upon activation and their roles in human disease. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
49. Renal proximal tubular epithelial cells exert immunomodulatory function by driving inflammatory CD4+T cell responses
- Author
-
Catherine Meyer-Schwesinger, Ulf Panzer, Tobias B. Huber, Katrin Neumann, Gisa Tiegs, Florian Grahammer, Philippe Christophe Breda, and Thorsten Wiech
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Cd4 t cell ,Physiology ,Crescentic glomerulonephritis ,Chemistry ,Antigen presentation ,Compartment (chemistry) ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Close contact ,Glomerular diseases ,Function (biology) ,030215 immunology - Abstract
In immune-mediated glomerular diseases like crescentic glomerulonephritis (cGN), inflammatory CD4+T cells accumulate within the tubulointerstitial compartment in close contact to proximal and distal tubular epithelial cells and drive renal inflammation and tissue damage. However, whether renal epithelial cell populations play a role in the pathogenesis of cGN by modulating CD4+T cell responses is less clear. In the present study, we aimed to investigate the potential of renal epithelial cells to function as antigen-presenting cells, thereby stimulating CD4+T cell responses. Using a FACS-based protocol that allowed comparative analysis of cortical epithelial cell populations, we showed that particularly proximal tubular epithelial cells (PTECs) express molecules linked with antigen-presenting cell function, including major histocompatibility complex class II (MHCII), CD74, CD80, and CD86 in homeostasis and nephrotoxic nephritis, a murine model of cGN. Protein expression was visualized at the PTEC single cell level by imaging flow cytometry. Interestingly, we found inflammation-dependent regulation of epithelium-expressed CD74, CD80, and CD86, whereas MHCII expression was not altered. Antigen-specific stimulation of CD4+T cells by PTECs in vitro supported CD4+T cell survival and induced CD4+T cell activation, proliferation, and inflammatory cytokine production. In patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis, MHCII and CD74 were expressed by both proximal and distal tubules, whereas CD86 was predominantly expressed by proximal tubules. Thus, particularly PTECs have the potential to induce an inflammatory phenotype in CD4+T cells in vitro, which might also play a role in the pathology of immune-mediated kidney disease.
- Published
- 2019
50. Immune gene expression networks in sepsis: A network biology approach
- Author
-
Seungok Lee, Yonggoo Kim, Kyung Soo Kim, Myungshin Kim, Jaeeun Yoo, and Dong Wook Jekarl
- Subjects
Leukocyte migration ,CD3 Complex ,Physiology ,Complement System ,Gene Expression ,Datasets as Topic ,Adaptive Immunity ,Pediatrics ,Biochemistry ,Cell Signaling ,Immune Physiology ,Medicine and Health Sciences ,Membrane Receptor Signaling ,Gene Regulatory Networks ,Immune Response ,Antigen Presentation ,Multidisciplinary ,Immune System Proteins ,Protein-Tyrosine Kinases ,Acquired immune system ,Immune Receptor Signaling ,Prognosis ,Medicine ,Network Analysis ,Research Article ,Signal Transduction ,Computer and Information Sciences ,Science ,CD8 Antigens ,Immunology ,Receptors, Antigen, T-Cell ,Computational biology ,Biology ,Immune system ,Signs and Symptoms ,Sepsis ,Genetics ,Humans ,Platelet activation ,KEGG ,Adaptor Proteins, Signal Transducing ,Innate immune system ,Gene Expression Profiling ,Biology and Life Sciences ,Proteins ,Computational Biology ,Membrane Proteins ,Molecular Sequence Annotation ,Cell Biology ,Complement System Proteins ,Survival Analysis ,Acquired Immune System ,Immunity, Innate ,CD8A ,Gene expression profiling ,Gene Ontology ,Gene Expression Regulation ,Lymphocyte Specific Protein Tyrosine Kinase p56(lck) ,Immune System ,Clinical Medicine ,Transcriptome - Abstract
To study the dysregulated host immune response to infection in sepsis, gene expression profiles from the Gene Expression Omnibus (GEO) datasets GSE54514, GSE57065, GSE64456, GSE95233, GSE66099 and GSE72829 were selected. From the Kyoto Encyclopedia of Genes and Genomes (KEGG) immune system pathways, 998 unique genes were selected, and genes were classified as follows based on gene annotation from KEGG, Gene Ontology, and Reactome: adaptive immunity, antigen presentation, cytokines and chemokines, complement, hematopoiesis, innate immunity, leukocyte migration, NK cell activity, platelet activity, and signaling. After correlation matrix formation, correlation coefficient of 0.8 was selected for network generation and network analysis. Total transcriptome was analyzed for differentially expressed genes (DEG), followed by gene set enrichment analysis. The network topological structure revealed that adaptive immunity tended to form a prominent and isolated cluster in sepsis. Common genes within the cluster from the 6 datasets included CD247, CD8A, ITK, LAT, and LCK. The clustering coefficient and modularity parameters were increased in 5/6 and 4/6 datasets in the sepsis group that seemed to be associated with functional aspect of the network. GSE95233 revealed that the nonsurvivor group showed a prominent and isolated adaptive immunity cluster, whereas the survivor group had isolated complement-coagulation and platelet-related clusters. T cell receptor signaling (TCR) pathway and antigen processing and presentation pathway were down-regulated in 5/6 and 4/6 datasets, respectively. Complement and coagulation, Fc gamma, epsilon related signaling pathways were up-regulated in 5/6 datasets. Altogether, network and gene set enrichment analysis showed that adaptive-immunity-related genes along with TCR pathway were down-regulated and isolated from immune the network that seemed to be associated with unfavorable prognosis. Prominence of platelet and complement-coagulation-related genes in the immune network was associated with survival in sepsis. Complement-coagulation pathway was up-regulated in the sepsis group that was associated with favorable prognosis. Network and gene set enrichment analysis supported elucidation of sepsis pathogenesis.
- Published
- 2021
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.