Human transporters associated with antigen processing (TAPs) select epitope precursor peptides for processing in the endoplasmic reticulum and presentation to T cells

Grégoire Lauvau, Kazuhiro Kakimi, Gabriele Niedermann, Marina Ostankovitch, Patricia Yotnda, Hüseyin Firat, Francis V. Chisari, Peter M. Van Endert

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Antigen presentation by major histocompatibility complex (MHC) class I molecules requires peptide supply by the transporters associated with antigen processing (TAPs), which select substrates in a species- and, in the rat, allele-specific manner. Conflicts between TAPs and MHC preferences for COOH- terminal peptide residues in rodent cells strongly reduce the efficiency of MHC class I antigen presentation. Although human TAP is relatively permissive, some peptide ligands for human histocompatibility leukocyte antigen class I molecules are known to possess very low TAP affinities; the significance of these in vitro findings for cellular antigen presentation is not known. We studied two naturally immunodominant viral epitopes presented by HLA-A2 that display very low affinities for human TAP. Low TAP affinities preclude minimal epitope access to the endoplasmic reticulum (ER) and assembly with HLA-A2 in vitro, as well as presentation by minigene-expressing cells to cytotoxic T lymphocytes. However, NH2-terminally but not COOH- terminally extended epitope variants with higher TAP affinities assemble in vitro and are presented to cytotoxic T lymphocytes with high efficiency. Thus, human TAP can influence epitope selection and restrict access to the ER to epitope precursors. Analysis of TAP affinities of a panel of viral epitopes suggests that TAP selection of precursors may be a common phenomenon for HLA-A2-presented epitopes. We also analyzed HLA-A2-eluted peptides from minigene-expressing cells and show that an NH2-terminally extended variant with low A2 binding affinity undergoes ER processing, whereas another with high affinity is presented unmodified. Therefore, the previously reported aminopeptidase activity in the ER can also act on TAP-translocated peptides.

Original languageEnglish (US)
Pages (from-to)1227-1239
Number of pages13
JournalJournal of Experimental Medicine
Volume190
Issue number9
DOIs
StatePublished - Nov 1 1999
Externally publishedYes

Keywords

  • ABC transporters
  • Aminopeptidases
  • Antigen presentation
  • HLA class I
  • Immunodominant epitopes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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