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Rates of Processing Determine the Immunogenicity of Immunoproteasome-Generated Epitopes¹

Parampal Deol^2,*, Dietmar M. W. Zaiss^2,*, John J. Monaco and Alice J. A. M. Sijts^3,

^* D. Smith Center for Vaccine Biology and Immunology and Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642; and Department of Molecular Genetics, University of Cincinnati, Cincinnati, OH 45267

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--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/i5 and MECL-1/i2, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Howard Hughes Biomedical Research Support Program for Medical Schools and National Institutes of Health Grant AI064576 (to A.S.) and by the German Research Council (DFG Za 280 to D.Z.).

² P.D. and D.M.W.Z. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. A. Sijts, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands. E-mail address: E.J.A.M.Sijts{at}vet.uu.nl

⁴ Abbreviations used in this paper: BM, bone marrow; DC, dendritic cell; LMP, low-molecular-mass polypeptide; MECL-1, multicatalytic endopeptidase complex-like-1; pAPC, professional APC; rLM, recombinant Listeria monocytogenes; i, induced.

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