Effects of Class II/CLIP Affinity on the Class II Antigen Presentation Pathway in the Context of Autoimmunity
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Hypocrellin A has gained much attention in recent years due to its light-induced antitumor, antifungal and antiviral activities. Here we report that hypocrellin A exerts immunomodulatory effects on MHC-restricted presentation of antigen. Hypocrellin A inhibited class II-MHC restricted presentation of exogenous antigen, but not class I MHC-restricted presentation of exogenous antigen, in dendritic cells. Hypocrellin A also inhibited the cytosolic pathway of endogenous antigen presentation. However, hypocrellin A did not inhibit the expression of class I and class II MHC molecules on dendritic cells (DCs), the phagocytic activity of DCs, or the H-2K(b)-restricted presentation of a synthetic peptide, SIINFEKL. These results show that hypocrellin A differentially modulates the MHC-restricted antigen presentation pathways.
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Abstract There is an antigen presenting cell (APC) in the lymphoid organs capable of presenting exogenous antigen (Ag) with major histocompatibility complex (MHC) class I molecules. This study was initiated to isolate clones of these APC to definitively establish their phenotype and to further study their properties. Murine bone marrow macrophages (BM MΦ) were immortalized by overexpressing myc and raf oncogenes. Five BM MΦ cell lines were generated that are phagocytic and expressed at their surface MΦ differentiation Ag. All five cell lines processed and presented exogenous ovalbumin (OVA) with MHC class I molecules. They all presented OVA‐linked to a phagocytic substrate 10 2 –10 4 ‐fold more efficiently than soluble Ag. Clonal isolates of two of the MΦ cell lines had an identical phenotype and functional properties as the uncloned lines. These results definitively establish that MΦ are APC with the capacity of presenting exogenous Ag with MHC class I molecules. Interferon (IFN)‐γ interleukin‐4, granulocyte‐macrophage colony stimulating factor and lipopolysaccharide either alone or in combination induced little or no augmentation and in some cases decreased presentation of exogenous OVA with MHC class I. In contrast, all of MΦ activating factors increased MHC class I expression. Moreover, IFN‐γ increased the presentation of cytosolic OVA, demonstrating differences between the presentation of cytosolic Ag versus exogenous Ag with MHC class I. Finally, some lines constitutively processed and presented exogenous OVA with MHC class II while others only presented after stimulation with IFN‐γ. These results demonstrate that the pathways involved in the presentation of exogenous Ag with MHC class I and class II are independently regulated and that a cloned cell is capable of presenting exogenous Ag through both pathways.
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The non-obese diabetic (NOD) mouse is a good model of insulin-dependent diabetes mellitus. Autoreactive T cells may play a fundamental role in disease initiation in this model, while disregulation of such cells may result from an abnormal thymic microenvironment. Diabetes is prevented in NOD mice by direct introduction of an E alpha d transgene (NOD-E) or a modified I-A beta chain of NOD origin (NOD-PRO or NOD-ASP). To investigate if disease pathology in NOD mice, protection from disease in transgenic NOD-E and NOD-PRO and partial protection from disease in NOD-ASP can be attributed to alterations in the thymic microenvironment, immunohistochemical and flow cytometric analysis of the thymi of these mouse strains was studied. Thymi from NOD and NOD-E mice showed a progressive increase in thymic B-cell percentage from 12 weeks of age. This was accompanied by a concomitant loss in thymic epithelial cells with the appearance of large epithelial-free areas mainly at the corticomedullary junction, which increased in size and number with age and contained the B-cell clusters. Such thymic B cells did not express CD5 and were absent in CBA, NOD-ASP and NOD-PRO mice as were the epithelial cell-free spaces, even at 5 months of age. Therefore the mechanisms of disease protection in the transgenic NOD-E and NOD-ASP/NOD-PRO mice may differ if these thymic abnormalities are related to disease.
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Peptides presented by MHC class I molecules are mostly derived from proteins synthesized by the antigen‐presenting cell itself, while peptides presented by MHC class II molecules are predominantly from materials acquired by endocytosis. External antigens can also be presented by MHC class I molecules in a process referred to as cross‐presentation. Here, we report that mouse dendritic cell (DC) engagement to a phagocytic target alters endocytic processing and inhibits the proteolytic activities. During phagocytosis, endosome maturation is delayed, shows less progression toward the lysosome, and the endocytosed soluble antigen is targeted for MHC class I cross‐presentation. The antigen processing in these arrested endosomes is under the control of NAPDH oxidase associated ROS. We also show that cathepsin S is responsible for the generation of the MHC class I epitope. Taken together, our results suggest that in addition to solid structure uptake, DC phagocytosis simultaneously modifies the kinetics of endosomal trafficking and maturation. As a consequence, external soluble antigens are targeted into the MHC class I cross‐presentation pathway.
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Conference Article| August 01 1995 Endogenous pathway of class II presentation G. Aichinger; G. Aichinger 1Department of Immunology, RPMS, Hammersmith Hospital, Du Cane Road, London W12 0NN, U.K. Search for other works by this author on: This Site PubMed Google Scholar R. I. Lechler R. I. Lechler * 1Department of Immunology, RPMS, Hammersmith Hospital, Du Cane Road, London W12 0NN, U.K. *To whom correspondence should be addressed Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Received: March 08 1995 Online ISSN: 1470-8752 Print ISSN: 0300-5127 © 1995 Biochemical Society1995 Biochem Soc Trans (1995) 23 (3): 657–660. https://doi.org/10.1042/bst0230657 Article history Received: March 08 1995 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation G. Aichinger, R. I. Lechler; Endogenous pathway of class II presentation. Biochem Soc Trans 1 August 1995; 23 (3): 657–660. doi: https://doi.org/10.1042/bst0230657 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: BFA, brefeldin A, ER, endoplasmic reticulum, HA, haemagglutinin, MHC, major histocompatability complex, TAP, transporter associated with antigen presentation, TGN, trans-Golgi network This content is only available as a PDF. © 1995 Biochemical Society1995 Article PDF first page preview Close Modal You do not currently have access to this content.
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IFN-γ is an important cytokine in resistance to infection with Listeria monocytogenes, and interleukin 10 is known to exacerbate infection with Listeria and other intracellular pathogens. We examined the effects of these cytokines on antigen presentation by macrophages infected with live Listeria. Listeriolysin O, a hemolysin secreted by Listeria, is an immunodominant antigen presented by both class I and class II MHC on infected cells. Thioglycollate-elicited macrophages were pretreated with exogenous IFN-γ, IL-10, or both cytokines overnight, infected with bacteria, and then fixed. Epitope-specific, MHC-restricted, T cell hybridomas were then added to detect the presentation of the class I or class II ligand. We found that IFN-γ enhanced the presentation of both the class I and class II epitopes and IL-10 strongly inhibited the presentation of both ligands. The degree of inhibition of presentation caused by IL-10 was dose dependent. IL-10 was also able to inhibit the presentation of exogenously added class II-binding peptide but had a less dramatic effect on the presentation of the added class I-binding polypeptide epitope. Flow cytometric analysis of expression of class I and class II on treated macrophaes demonstrated that the inhibitory effect of IL-10 on antigen presentation was not due to significant downregulation of MHC expression. This loss of antigen presentation was also not due to downregulation of the costimulatory molecule, B7-2. We have found that IFN-γ and IL-10 have opposing immunoregulatory effects on the presentation of antigens derived from an intracellular pathogen and that the class I vs. class II-mediated presentation of antigens is differentially regulated by IL-10.
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