An Unexpected Major Role for Proteasome-Catalyzed Peptide Splicing in Generation of T Cell Epitopes: Is There Relevance for Vaccine Development?

Anouk C M Platteel,Willem Van Eden,Juliane Liepe,Michele Mishto,Alice J A M Sijts

doi:10.3389/fimmu.2017.01441

Abstract

Efficient and safe induction of CD8+ T cell responses is a desired characteristic of vaccines against intracellular pathogens. To achieve this, a new generation of safe vaccines is being developed accommodating single, dominant antigens of pathogens of interest. In particular, the selection of such antigens is challenging, since due to HLA polymorphism the ligand specificities and immunodominance hierarchies of pathogen-specific CD8+ T cell responses differ throughout the human population. A recently discovered mechanism of proteasome-mediated CD8+ T cell epitope generation, i.e., by proteasome-catalyzed peptide splicing (PCPS), expands the pool of peptides and antigens, presented by MHC class I HLA molecules. On the cell surface, one-third of the presented self-peptides are generated by PCPS, which coincides with one-fourth in terms of abundance. Spliced epitopes are targeted by CD8+ T cell responses during infection and, like non-spliced epitopes, can be identified within antigen sequences using a novel in silico strategy. The existence of spliced epitopes, by enlarging the pool of peptides available for presentation by different HLA variants, opens new opportunities for immunotherapies and vaccine design.

Highlights

Infection with most viruses and bacteria elicits a protective immune response that eradicates the pathogen and provides immunity to subsequent infections
Peptide fragments released from the proteasome may bind the transporter associated with antigen processing (TAP) for translocation into the ER
We showed that CD8+ T cells, specific for an immunodominant epitope derived from the listeriolysin O antigen, cross-recognized an overlapping peptide produced by proteasome-mediated splicing of the LLO sequence (Figure 2A) [24]

Summary

INTRODUCTION

Infection with most viruses and bacteria elicits a protective immune response that eradicates the pathogen and provides immunity to subsequent infections. Advanced prediction programs exist for the identification of such epitopes, a larger percentage of proteins seem not to contain any epitope candidates that may trigger a protective T cell response In this mini review, we will focus on a recently discovered mechanism underlying T cell-mediated immune recognition. Proteasomes, the proteases that generate most peptide epitopes presented to CD8+ T cells [1], degrade proteins and paste non-contiguous sequences of a given antigen back together [2, 3]. This mechanism is called proteasome-catalyzed peptide splicing (PCPS) (Figure 1). We here discuss the opportunities and implications of PCPS for pathogen-specific immune protection and vaccine design

SIGNALING INVADERS

OF SPLICED EPITOPES

RELEVANCE OF PCPS FOR VACCINE DESIGN

Findings

AUTHOR CONTRIBUTIONS