NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing
| العنوان: | NADPH Oxidase Modifies Patterns of MHC Class II–Restricted Epitopic Repertoires through Redox Control of Antigen Processing |
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| المؤلفون: | Dale R. Balce, Euan R.O. Allan, Amy L. Warren, Payman Pirzadeh, Bernard Renaux, Robin M. Yates, Frank R. Jirik, Pankaj Tailor, Neil McKenna |
| المصدر: | The Journal of Immunology. 192:4989-5001 |
| بيانات النشر: | The American Association of Immunologists, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, Encephalomyelitis, Autoimmune, Experimental, Cathepsin L, Proteolysis, Immunology, Antigen-Presenting Cells, Epitopes, T-Lymphocyte, Bone Marrow Cells, Epitope, Cell Line, Myelin oligodendrocyte glycoprotein, Mice, medicine, Animals, Immunology and Allergy, Mice, Knockout, MHC class II, Membrane Glycoproteins, NADPH oxidase, biology, medicine.diagnostic_test, Antigen processing, Macrophages, Experimental autoimmune encephalomyelitis, Histocompatibility Antigens Class II, Proteolytic enzymes, NADPH Oxidases, medicine.disease, Cathepsins, Molecular biology, NADPH Oxidase 2, biology.protein, Myelin-Oligodendrocyte Glycoprotein, Oxidation-Reduction |
| الوصف: | The chemistries within phagosomes of APCs mediate microbial destruction as well as generate peptides for presentation on MHC class II. The antimicrobial effector NADPH oxidase (NOX2), which generates superoxide within maturing phagosomes, has also been shown to regulate activities of cysteine cathepsins through modulation of the lumenal redox potential. Using real-time analyses of lumenal microenvironmental parameters, in conjunction with hydrolysis pattern assessment of phagocytosed proteins, we demonstrated that NOX2 activity not only affects levels of phagosomal proteolysis as previously shown, but also the pattern of proteolytic digestion. Additionally, it was found that NOX2 deficiency adversely affected the ability of bone marrow–derived macrophages, but not dendritic cells, to process and present the I-Ab–immunodominant peptide of the autoantigen myelin oligodendrocyte glycoprotein (MOG). Computational and experimental analyses indicated that the I-Ab binding region of the immunodominant peptide of MOG is susceptible to cleavage by the NOX2-controlled cysteine cathepsins L and S in a redox-dependent manner. Consistent with these findings, I-Ab mice that were deficient in the p47phox or gp91phox subunits of NOX2 were partially protected from MOG-induced experimental autoimmune encephalomyelitis and displayed compromised reactivation of MOG-specific CD4+ T cells in the CNS, despite eliciting a normal primary CD4+ T cell response to the inoculated MOG Ag. Taken together, this study demonstrates that the redox microenvironment within the phagosomes of APCs is a determinant in MHC class II repertoire production in a cell-specific and Ag-specific manner, which can ultimately impact susceptibility to CD4+ T cell–driven autoimmune disease processes. |
| تدمد: | 1550-6606 0022-1767 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c121fd95d009f587152e05fd75bdc099 https://doi.org/10.4049/jimmunol.1302896 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....c121fd95d009f587152e05fd75bdc099 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
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