Rates of processing determine the immunogenicity of immunoproteasome-generated epitopes

Parampal Deol, Dietmar M W Zaiss, John J Monaco, Alice J A M Sijts

    Research output: Contribution to journalArticleAcademicpeer-review

    Abstract

    CD8 T cells resolve intracellular pathogens by responding to pathogen-derived peptides that are presented on the cell surface by MHC class I molecules. Although most pathogens encode a large variety of antigenic peptides, protective CD8 T cell responses target usually only a few of these. To determine the mechanism by which the IFN-gamma-inducible proteasome (immuno) subunits enhance the ability of specific pathogen-derived peptides to elicit CD8 T cell responses, we generated a recombinant Listeria monocytogenes strain (rLM-E1) that secretes a model Ag encompassing the immunoproteasome-dependent E1B(192-200) and immunoproteasome-independent E1A(234-243) epitope. Analyses of Ag presentation showed that infected gene-deficient professional APCs, lacking the immunosubunits LMP7/ibeta5 and MECL-1/ibeta2, processed and presented the rLM-E1-derived E1B(192-200) epitope but with delayed kinetics. E1A epitope processing proceeded normally in these cells. Accordingly, infected gene-deficient mice failed to respond to the otherwise immunodominant E1B(192-200) epitope but mounted normal CD8 T cell responses to E1A(234-243) which was processed by the same professional APCs, from the same rLM-E1 Ag. The inability of gene-deficient mice to respond to E1B(192-200) was not explained by insufficient quantities of antigenic peptide, as splenic APC of 36-h-infected gene-deficient mice that presented the two E1 epitopes at steady state levels elicited responses to both E1B(192-200) and E1A(234-243) when transferred into LMP7+MECL-1-deficient mice. Taken together, our findings indicate that not absolute epitope quantities but early Ag-processing kinetics determine the ability of pathogen-derived peptides to elicit CD8 T cell responses, which is of importance for rational T cell vaccine design.

    Original languageEnglish
    Pages (from-to)7557-7562
    Number of pages6
    JournalJournal of Immunology
    Volume178
    Issue number12
    DOIs
    Publication statusPublished - 15 Jun 2007

    Keywords

    • Amino Acid Sequence
    • Animals
    • Antigen Presentation
    • Antigen-Presenting Cells
    • Antigens, Bacterial
    • CD8-Positive T-Lymphocytes
    • Cysteine Endopeptidases
    • Dendritic Cells
    • Epitopes
    • Kinetics
    • Listeria monocytogenes
    • Mice
    • Mice, Mutant Strains
    • Molecular Sequence Data
    • Multienzyme Complexes
    • Peptides
    • Proteasome Endopeptidase Complex
    • Journal Article
    • Research Support, N.I.H., Extramural
    • Research Support, Non-U.S. Gov't

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