Influenza A virus infection-induced macroautophagy facilitates MHC class II-restricted endogenous presentation of an immunodominant viral epitope.

Autor: Deng J; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia., Lu C; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia.; School of Medicine, Deakin University, Waurn Ponds, Vic., Australia., Liu C; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia., Oveissi S; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia., Fairlie WD; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia.; Olivia Newton-John Cancer Research Institute, Heidelberg, Vic., Australia.; School of Cancer Medicine, La Trobe University, Melbourne, Vic., Australia., Lee EF; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia.; Olivia Newton-John Cancer Research Institute, Heidelberg, Vic., Australia.; School of Cancer Medicine, La Trobe University, Melbourne, Vic., Australia., Bilsel P; FluGen Inc., Madison, WI, USA., Puthalakath H; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia., Chen W; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Vic., Australia.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2021 May; Vol. 288 (10), pp. 3164-3185. Date of Electronic Publication: 2020 Dec 18.
DOI: 10.1111/febs.15654
Abstrakt: 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 NP 311-325 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.
(© 2020 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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