Endogenous MHC Class II Processing of a Viral Nuclear Antigen After Autophagy

Science 307: 593-596.

Speaker : 鄭達恩                           Time: 14:00-15:00 March 9, 2005

Commentator : 呂政展 老師                               Place: Room 601

Abstract :

Epstein-Barr virus (EBV), which infects more than 90% of the human adult population, establishes life-long latency in memory B cells and is associated with many important tumors, like Hodgkin’s disease and nasopharyngeal carcinoma. In its latency phase, a protein is needed to allow viral DNA attaching to host chromosome in proliferating cells which is called EBV nuclear antigen 1(EBNA1). EBNA1 is expressed in all EBV-associated tumors and EBV-positive proliferating cells in healthy EBV carriers, but it contains a Gly-Ala repeat domain which was found to prevent antigen processing for cytolytic CD8⁺ T cell recognition. In recent studies nearly all healthy EBV carriers were found to mount a CD4⁺ T cell response to this antigen, suggesting that EBNA1 might be vital for major histocompatibility complex (MHC) class II presentation (1). How is an endogenous antigen presented by MHC class II? The authors showed that autophagy might be the major mechanism. First, the authors demonstrated that EBNA1 accumulates in cytosol with a lysosome marker, lysosome-associated membrane protein 1 (LAMP1) after inhibition of lysosomal acidification. Next, the authors localized EBNA1 in autophagosomes upon inhibition of lysosomal acidification. Base on these two results, the authors hypothesize that EBNA1 would be degraded by autophagy (2). Furthermore, the authors blocked autophagy by an autophagy inhibitor 3-methyladenine and siRNA of Atg12, an important component in autophagy that leads to decrease of IFN-g response of EBNA1-specific CD4⁺ T cells but has no effect on EBNA3-specific CD8⁺ T cells. Above all, the authors showed a novel mechanism in antigen presentation and a new aspect on vaccine development.

References :

1. Khanna, R., S.R. Burrows, P.M. Steigerwald-Mullen, D.J. Moss, M.G. Kurilla, and L. Cooper. 1997. Targeting Epstein-Barr virus nuclear antigen 1 (EBNA1) through the class II pathway restores immune recognition by EBNA1-specific cytotoxic T lymphocytes: evidence for HLA-DM-independent processing. Int. Immunol. 9:1537–1543.

2. Yeo, M., Lee, S.K., Lee, B., E.C. Ruiz, S.L. Pfaff, and G.N. Gill. 2005. Endogenous MHC Class II Processing of a Viral Nuclear Antigen After Autophagy. Science 307: 593-596.