Autophagy enhances the presentation of endogenous viral antigens on MHC class I molecules during HSV-1 infection

English, L., et al. 2009. Nature Immunology 10, 480-487

Speaker: Alan Hsu (許翊輝)                                                 Time: 14:10~15:00, Dec. 9, 2009

Commentator: Dr. Hsiao-Sheng Liu (劉校生老師)              Place: Room 601

Abstract:

        Autophagy a process well known for clearing cellular proteins and unused components by fusing with lytic vacuoles and targeting them for degradation has been reported to  play an important role in helping the clearance of intracellular pathogens¹. Here the authors present a model where autophagy, this “janitor” of the cell can be lined up with the combatants and arsenal of the cell playing a crucial role in presenting HSV-1 glycoprotein B (gB) to CD8⁺ T cells. By mediating presentation of MHC-I molecules during later infection, compared with the initial stage of infection where the traditional MHC-I pathway still dominates. This “dual” scenario occurs throughout different stages and of infection. The authors also noted a type of previously unknown form of autophagic bodies. Unlike previous types of common morphological autophagic bodies; this autophagosome which participates in viral clearance originates from the nuclear envelope and endoplasmic reticulum, and forms a “four layer” structure. It was confirmed to be an autophagic body by colocalization of LC3 positive properties and gB proteins. Further evidence was provided when BSA-gold particles were transferred from lysosomes to these “newly found” structures. By using inhibitors of autophagy; Bafilomycin A ,Atg5 siRNA, and 3-MA each blocking autophagy at a different level clearly showed that this “self clearance” pathway intersects with endogenous antigen presentation route in later infection time points where they had mild or no effect during early infection. To emphasize on the role of autophagy in gB peptide presentation, the usage of a mutant HSV-1 strain(△34.5) which was previously known unable to inhibit macroautophagy, stimulated CD8⁺ T cells through a distinct pathway from the wild type virus. While distinct pathways all leading to intracellular antigen presentation by MHC-I, they have very discrete cytokine profiles. The traditional pathway inducing IFN-γcan stimulate CD8⁺ T cells very efficiently, but not going through the autophagy pathway, and thus is not effected by autophagy inhibitors. On the other hand, infected cells treated with heat shock, IL-1β, present the antigen through the autophagic pathway, and is sensitive to autophagic inhibitors.

References:

1. Levine, B. & Deretic, V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat. Rev. Immunol. 7, 767–777 (2007).
2. Alexander, D.E., Ward, S.L., Mizushima, N., Levine, B. & Leib, D.A. Analysis of the role of autophagy in replication of herpes simplex virus in cell culture. J. Virol. 81, 12128–12134 (2007