Research on the Mechanism by which Influenza A Virus Induces Autophagy to Promote Endogenous Antigen Presentation by MHC Class II Molecules

Influenza A virus (IAV) poses a significant global public health threat, annually causing millions of infections and hundreds of thousands of deaths worldwide. Its high mutation rate and cross-species transmission capacity present persistent challenges to vaccine development efforts.

Immunity/InflammaInfluenza A virus MHC class II molecule Influenza A virus
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Influenza A virus infection-induced macroautophagy facilitates MHC class II-restricted endogenous presentation of an immunodominant viral epitope

Introduction

Influenza A virus (IAV), a major global health threat, causes millions of infections and hundreds of thousands of deaths annually. Its high mutation rate and cross - species transmissibility pose持续 challenges for vaccine development. Traditionally, MHC class II molecules were thought to present exogenous antigens, while MHC class I molecules handled endogenous ones. Recent studies show that viruses can blur this line via mechanisms like autophagy. A 2021 FEBS Journal study found that IAV - induced autophagy enhances endogenous antigen presentation by MHC class II molecules, offering new insights into influenza immunity.

Research Background and Significance
Autophagy, a lysosome - mediated degradation process, can both eliminate pathogens and be exploited by viruses for replication. Earlier studies indicated autophagy could influence MHC class I presentation, but its role in MHC class II pathways was unclear. Given that MHC class II cross - presentation of endogenous antigens can activate CD4+ T cells, this study, using IAV infection models, demonstrates that autophagy bridges viral endogenous antigens and MHC class II presentation, providing new targets for flu vaccine design.
Research Content and Methods
  1. Virus Model and Cell System
The study used the A/PR/8/34 (H1N1) IAV strain to infect mouse bone marrow - derived dendritic cells (BMDCs) and human monocyte - derived dendritic cells (moDCs), mimicking natural infection. As professional antigen - presenting cells, dendritic cells are crucial for initiating T - cell responses.
  1. Autophagy Intervention
Chemical inhibitors: 3 - MA blocked autophagosome formation, and E64d inhibited lysosomal degradation. Gene knockout: CRISPR/Cas9 was used to create Beclin1 and Atg7 knockout cell lines, targeting autophagy initiation and autophagosome elongation respectively.
  1. Antigen Presentation Detection
Flow cytometry: MHC class II (I - Ab) tetramers labeled NP311 - 325 - specific CD4+ T cells to quantify antigen - specific T - cell activation. Confocal microscopy: Observed LC3 and MHC class II compartment (MIIC) co - localization to verify autophagosome - MIIC fusion. Protein synthesis inhibition: CHX blocked new protein synthesis to assess antigen presentation's dependence on new antigens.
  1. Molecular Mechanism Analysis
ER - Golgi blockade: BFA inhibited protein transport to evaluate the secretory pathway's role in antigen presentation. TAP - deficient model: TAP1 - knockout cells assessed whether antigen presentation relied on the transporter associated with antigen processing (TAP).
Results
  1. IAV Infection Induces Autophagy - dependent Antigen Presentation
IAV infection increased LC3 - II levels in BMDCs, indicating autophagy activation. NP311 - 325 - specific CD4+ T - cell activation dropped by 60% - 70% with autophagy inhibitors or in gene - knockout cells, showing autophagy's crucial role in MHC class II endogenous antigen presentation.
  1. Antigen Presentation Depends on New Protein Synthesis and the Secretory Pathway
CHX reduced antigen presentation by 85%, and BFA completely blocked it, indicating that antigen presentation required newly synthesized antigens and MHC class II molecules transported via the ER - Golgi network to MIIC.
  1. Direct Evidence of Autophagosome - MIIC Fusion
Confocal microscopy showed a three - fold increase in LC3 - labeled autophagosome and MIIC co - localization post - IAV infection, eliminated by autophagy inhibitors. Antigen presentation enhanced in TAP - deficient cells suggested some antigens originated from cytosolic proteins, possibly delivered to MIIC via autophagosomes.
  1. Mechanism of Autophagy Blocking Autophagosome - Lysosome Fusion
IAV infection inhibited Rab7 GTPase activity, blocking autophagosome - lysosome fusion and promoting autophagosome - MIIC interaction. This prolonged antigen residence in MIIC, enhancing processing efficiency.
Discussion and Conclusions
  1. Theoretical Breakthrough: Autophagy Restructures MHC Class II Antigen Presentation
The study challenges the traditional view by showing that IAV - induced autophagy delivers endogenous viral proteins (e.g., NP311 - 325) to MIIC for MHC class II presentation, offering a new paradigm for understanding viral immune evasion and host defense.
  1. Immunological Significance: Enhanced CD4+ T - Cell Responses
MHC class II presentation of endogenous antigens activates CD4+ T cells, which coordinate immune responses via cytokines like IFN - γ. Lower CD4+ T - cell activation in autophagy - deficient cells indicates autophagy is key for flu - specific CD4+ T - cell responses.
  1. Implications for Vaccine Design: Targeting Autophagy Pathways
Current flu vaccines mainly induce neutralizing antibodies with limited cross - protection. This study suggests that activating autophagy to enhance MHC class II endogenous antigen presentation could lead to broader T - cell - inducing vaccines, such as combining viral antigens with autophagy inducers or designing adjuvants targeting autophagy molecules like Beclin1.
  1. Future Directions: Cross - Species Comparisons and Clinical Translation
The study's findings in mouse and human cells need validation across influenza subtypes and bat - derived IAV. Also, the safety of autophagy regulators must be assessed in animal models to explore new flu therapies.
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This article is reviewed and published by the technical expert team of UA

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