Rates of processing determine the immunogenicity of immunoproteasome-generated epitopes.
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.
Deol
Parampal
P
D. Smith Center for Vaccine Biology and Immunology, and Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.
Zaiss
Dietmar M W
DM
Monaco
John J
JJ
Sijts
Alice J A M
AJ
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D007700:Kinetics; D008089:Listeria monocytogenes / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics; D010455:Peptides / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*
D000942:Antigens, Bacterial; D000939:Epitopes; D009097:Multienzyme Complexes; D010455:Peptides; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C490920:Psmb10 protein, mouse