MHC class I antigen processing distinguishes endogenous antigens based on their translation from cellular vs. viral mRNA

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2012; 109(18):7025-30. DOI: 10.1073/pnas.1112387109
Source: PubMed


To better understand the generation of MHC class I-associated peptides, we used a model antigenic protein whose proteasome-mediated degradation is rapidly and reversibly controlled by Shield-1, a cell-permeant drug. When expressed from a stably transfected gene, the efficiency of antigen presentation is ~2%, that is, one cell-surface MHC class I-peptide complex is generated for every 50 folded source proteins degraded upon Shield-1 withdrawal. By contrast, when the same protein is expressed by vaccinia virus, its antigen presentation efficiency is reduced ~10-fold to values similar to those reported for other vaccinia virus-encoded model antigens. Virus infection per se does not modify the efficiency of antigen processing. Rather, the efficiency difference between cellular and virus-encoded antigens is based on whether the antigen is synthesized from transgene- vs. virus-encoded mRNA. Thus, class I antigen-processing machinery can distinguish folded proteins based on the precise details of their synthesis to modulate antigen presentation efficiency.

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    • "Favoring the DRiPs model, viral epitopes for CTL have been shown to be generated from recently synthesized peptides, rather than from mature proteins, confirming the potential of this mechanism for altering the host peptide repertoire (71). Additionally, the efficiency of presentation of an epitope may depend on the source, viral or cellular, of the mRNA and there may also be compartmentalization in the subcellular localization of peptides for class I presentation (65, 72). "
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