Cytotoxic T lymphocyte epitopes of HIV-1 Nef: Generation of multiple definitive major histocompatibility complex class I ligands by proteasomes

Maria Lucchiari-Hartz, Peter M. Van Endert, Grégoire Lauvau, Reinhard Maier, Andreas Meyerhans, Derek Mann, Klaus Eichmann, Gabriele Niedermann

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Although a pivotal role of proteasomes in the proteolytic generation of epitopes for major histocompatibility complex (MHC) class I presentation is undisputed, their precise function is currently the subject of an active debate: do proteasomes generate many epitopes in definitive form, or do they merely generate the COOH termini, whereas the definitive NH2 termini are cleaved by aminopeptidases? We determined five naturally processed MHC class I ligands derived from HIV-1 Nef. Unexpectedly, the five ligands correspond to only three cytotoxic T lymphocyte (CTL) epitopes, two of which occur in two COOH-terminal length variants. Parallel analyses of proteasomal digests of a Nef fragment encompassing the epitopes revealed that all five ligands are direct products of proteasomes. Moreover, in four of the five ligands, the NH2 termini correspond to major proteasome cleavage sites, and putative NH2-terminally extended precursor fragments were detected for only one of the five ligands. All ligands are transported by the transporter associated with antigen processing (TAP). The combined results from these five ligands provide strong evidence that many definitive MHC class I ligands are precisely cleaved at both ends by proteasomes. Additional evidence supporting this conclusion is discussed, along with contrasting results of others who propose a strong role for NH2-terminal trimming with direct proteasomal epitope generation being a rare event.

Original languageEnglish (US)
Pages (from-to)239-252
Number of pages14
JournalJournal of Experimental Medicine
Volume191
Issue number2
DOIs
StatePublished - Jan 17 2000
Externally publishedYes

Keywords

  • Antigen processing
  • Cytotoxic T lymphocyte epitopes
  • HW Nef
  • Naturally processed peptides
  • Proteasome

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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