Viral Sequestration of Antigen Subverts Cross Presentation to CD8+ T Cells

PLoS Pathogens

Jean M. Grant¹  Eric F. Tewalt¹  Christopher C. Norbury¹  Erica L. Granger¹  Neal D. Heuss²  Dale S. Gregerson²  Douglas C. Palmer³  Nicholas P. Restifo³ 

[1] Department of Microbiology and Immunology, Pennsylvania State University, Milton S. Hershey College of Medicine, Hershey, Pennsylvania, United States of America;Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota, United States of America;Surgery Branch and Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Antigen presentation;    Major histocompatibility complex;    Cloning;    T cells;    Cell staining;    Antigens;    T cell receptors;    Vaccinia virus;   

DOI  :  10.1371/journal.ppat.1000457

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Virus-specific CD8+ T cells (TCD8+) are initially triggered by peptide-MHC Class I complexes on the surface of professional antigen presenting cells (pAPC). Peptide-MHC complexes are produced by two spatially distinct pathways during virus infection. Endogenous antigens synthesized within virus-infected pAPC are presented via the direct-presentation pathway. Many viruses have developed strategies to subvert direct presentation. When direct presentation is blocked, the cross-presentation pathway, in which antigen is transferred from virus-infected cells to uninfected pAPC, is thought to compensate and allow the generation of effector TCD8+. Direct presentation of vaccinia virus (VACV) antigens driven by late promoters does not occur, as an abortive infection of pAPC prevents production of these late antigens. This lack of direct presentation results in a greatly diminished or ablated TCD8+ response to late antigens. We demonstrate that late poxvirus antigens do not enter the cross-presentation pathway, even when identical antigens driven by early promoters access this pathway efficiently. The mechanism mediating this novel means of viral modulation of antigen presentation involves the sequestration of late antigens within virus factories. Early antigens and cellular antigens are cross-presented from virus-infected cells, as are late antigens that are targeted to compartments outside of the virus factories. This virus-mediated blockade specifically targets the cross-presentation pathway, since late antigen that is not cross-presented efficiently enters the MHC Class II presentation pathway. These data are the first to describe an evasion mechanism employed by pathogens to prevent entry into the cross-presentation pathway. In the absence of direct presentation, this evasion mechanism leads to a complete ablation of the TCD8+ response and a potential replicative advantage for the virus. Such mechanisms of viral modulation of antigen presentation must also be taken into account during the rational design of antiviral vaccines.

【 授权许可】

CC BY