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A large fraction of HLA class I ligands are proteasome-generated spliced peptides

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Science  21 Oct 2016:
Vol. 354, Issue 6310, pp. 354-358
DOI: 10.1126/science.aaf4384

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New players in the repertoire

Antigen-presenting cells, such as macrophages and dendritic cells, activate immunological T cells by presenting them with antigens bound by major histocompatibility complexes (MHCs). The proteasome typically processes these antigens, which include peptides derived from both self and microbial origins. Liepe et al. now report that, surprisingly, a large fraction of peptides bound to class I MHC on multiple human cell types are spliced together by the proteasome from two different fragments of the same protein. Such merged peptides might turn out to be useful in vaccine or cancer immunotherapy development.

Science, this issue p. 354

Abstract

The proteasome generates the epitopes presented on human leukocyte antigen (HLA) class I molecules that elicit CD8+ T cell responses. Reports of proteasome-generated spliced epitopes exist, but they have been regarded as rare events. Here, however, we show that the proteasome-generated spliced peptide pool accounts for one-third of the entire HLA class I immunopeptidome in terms of diversity and one-fourth in terms of abundance. This pool also represents a unique set of antigens, possessing particular and distinguishing features. We validated this observation using a range of complementary experimental and bioinformatics approaches, as well as multiple cell types. The widespread appearance and abundance of proteasome-catalyzed peptide splicing events has implications for immunobiology and autoimmunity theories and may provide a previously untapped source of epitopes for use in vaccines and cancer immunotherapy.

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