Influenza A virus infection‐induced macroautophagy facilitates MHC class II‐restricted endogenous presentation of an immunodominant viral epitope
| Autor: | Erinna F. Lee, Deng Jieru, Pamuk Bilsel, W. Douglas Fairlie, Hamsa Puthalakath, Chunni Lu, Weisan Chen, Sara Oveissi, Chuanxin Liu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Antigen presentation Gene Expression Bone Marrow Cells Endogeny Cycloheximide Transfection medicine.disease_cause Autophagy-Related Protein 7 Biochemistry Article Epitope Mice 03 medical and health sciences chemistry.chemical_compound Influenza A Virus H1N1 Subtype 0302 clinical medicine Orthomyxoviridae Infections Antigen Macroautophagy Influenza A virus medicine Animals Humans Antigens Viral Molecular Biology Antigen Presentation MHC class II Brefeldin A biology Immunodominant Epitopes Autophagy Histocompatibility Antigens Class II Dendritic Cells Cell Biology Virology Mice Inbred C57BL HEK293 Cells 030104 developmental biology chemistry 030220 oncology & carcinogenesis Host-Pathogen Interactions biology.protein Beclin-1 Female Plasmids |
| Zdroj: | FEBS J |
| ISSN: | 1742-4658 1742-464X |
| Popis: | CD4+ T cells recognize peptides presented by major histocompatibility complex class II molecules (MHC-II). These peptides are generally derived from exogenous antigens. Macroautophagy has been reported to promote endogenous antigen presentation in viral infections. However, whether influenza A virus (IAV) infection-induced macroautophagy also leads to endogenous antigen presentation through MHC-II is still debated. In this study, we show that IAV infection leads to endogenous presentation of an immunodominant viral epitope NP311-325 by MHC-II to CD4+ T cells. Mechanistically, such MHC-II-restricted endogenous IAV antigen presentation requires de novo protein synthesis as it is inhibited by the protein synthesis inhibitor cycloheximide, and a functional ER-Golgi network as it is totally blocked by Brefeldin A. These results indicate that MHC-II-restricted endogenous IAV antigen presentation is dependent on de novo antigen and/or MHC-II synthesis, and transportation through the ER-Golgi network. Furthermore, such endogenous IAV antigen presentation by MHC-II is enhanced by TAP deficiency, indicating some antigenic peptides are of cytosolic origin. Most importantly, the bulk of such MHC-II-restricted endogenous IAV antigen presentation is blocked by autophagy inhibitors (3-MA and E64d) and deletion of autophagy-related genes, such as Beclin1 and Atg7. We have further demonstrated that in dendritic cells, IAV infection prevents autophagosome-lysosome fusion and promotes autophagosome fusion with MHC class II compartment (MIIC), which likely promotes endogenous IAV antigen presentation by MHC-II. Our results provide strong evidence that IAV infection-induced autophagosome formation facilitates endogenous IAV antigen presentation by MHC-II to CD4+ T cells. The implication for influenza vaccine design is discussed. |
| Databáze: | OpenAIRE |
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