tetano
Editor, Senior Moderator
FEBS J
. 2020 Dec 5.
doi: 10.1111/febs.15654. Online ahead of print.
Influenza A virus infection-induced macroautophagy facilitates MHC class II-restricted endogenous presentation of an immunodominant viral epitope
Jieru Deng[SUP] 1 [/SUP], Chunni Lu[SUP] 1 2 [/SUP], Chuanxin Liu[SUP] 1 [/SUP], Sara Oveissi[SUP] 1 [/SUP], W Douglas Fairlie[SUP] 1 3 4 [/SUP], Erinna F Lee[SUP] 1 3 4 [/SUP], Pamuk Bilsel[SUP] 5 [/SUP], Hamsa Puthalakath[SUP] 1 [/SUP], Weisan Chen[SUP] 1 [/SUP]
Affiliations
Abstract
CD4[SUP]+[/SUP] 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[SUB]311-325[/SUB] by MHC-II to CD4[SUP]+[/SUP] 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[SUP]+[/SUP] T cells. The implication for influenza vaccine design is discussed.
Keywords: CD4+ T cell; MHC?II; antigen presentation; influenza A virus; macroautophagy.
. 2020 Dec 5.
doi: 10.1111/febs.15654. Online ahead of print.
Influenza A virus infection-induced macroautophagy facilitates MHC class II-restricted endogenous presentation of an immunodominant viral epitope
Jieru Deng[SUP] 1 [/SUP], Chunni Lu[SUP] 1 2 [/SUP], Chuanxin Liu[SUP] 1 [/SUP], Sara Oveissi[SUP] 1 [/SUP], W Douglas Fairlie[SUP] 1 3 4 [/SUP], Erinna F Lee[SUP] 1 3 4 [/SUP], Pamuk Bilsel[SUP] 5 [/SUP], Hamsa Puthalakath[SUP] 1 [/SUP], Weisan Chen[SUP] 1 [/SUP]
Affiliations
- PMID: 33830641
- DOI: 10.1111/febs.15654
Abstract
CD4[SUP]+[/SUP] 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[SUB]311-325[/SUB] by MHC-II to CD4[SUP]+[/SUP] 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[SUP]+[/SUP] T cells. The implication for influenza vaccine design is discussed.
Keywords: CD4+ T cell; MHC?II; antigen presentation; influenza A virus; macroautophagy.