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

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.