Multi-level Strategy for Identifying Proteasome-Catalyzed Spliced Epitopes Targeted by CD8+ T Cells during Bacterial Infection

Publication date: 1 August 2017
Source:Cell Reports, Volume 20, Issue 5
Author(s): Anouk C.M. Platteel, Juliane Liepe, Kathrin Textoris-Taube, Christin Keller, Petra Henklein, Hanna H. Schalkwijk, Rebeca Cardoso, Peter M. Kloetzel, Michele Mishto, Alice J.A.M. Sijts
Proteasome-catalyzed peptide splicing (PCPS) generates peptides that are presented by MHC class I molecules, but because their identification is challenging, the immunological relevance of spliced peptides remains unclear. Here, we developed a reverse immunology-based multi-level approach to identify proteasome-generated spliced epitopes. Applying this strategy to a murine Listeria monocytogenes infection model, we identified two spliced epitopes within the secreted bacterial phospholipase PlcB that primed antigen-specific CD8⁺ T cells in L. monocytogenes-infected mice. While reacting to the spliced epitopes, these CD8⁺ T cells failed to recognize the non-spliced peptide parts in the context of their natural flanking sequences. Thus, we here show that PCPS expands the CD8⁺ T cell response against L. monocytogenes by exposing spliced epitopes on the cell surface. Moreover, our multi-level strategy opens up opportunities to systematically investigate proteins for spliced epitope candidates and thus strategies for immunotherapies or vaccine design.

Graphical abstract

Teaser

Proteasomes both degrade proteins and ligate generated products, creating "spliced peptides" composed of distant protein parts. Platteel et al. now describe a multi-level strategy for identifying proteasome-generated spliced T cell epitopes. This work suggests ways of defining spliced epitopes within any antigen of interest and to determine their immunological relevance.


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