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Peptides with dual binding specificity for HLA-A2 and HLA-E are encoded by alternatively spliced isoforms of the antioxidant enzyme peroxiredoxin 5.
- Source :
-
International immunology [Int Immunol] 2009 Mar; Vol. 21 (3), pp. 257-68. Date of Electronic Publication: 2009 Jan 30. - Publication Year :
- 2009
-
Abstract
- Peptides with dual binding specificity for classical HLA class I and non-classical HLA-E molecules have been identified in virus-encoded proteins, but not in cellular proteins from normal or neoplastic cells. Expression screening of a melanoma cDNA library with a CTL clone recognizing an HLA-A2-restricted tumor-specific epitope encoded by mutant peroxiredoxin 5 (Prdx5), a stress-inducible peroxidase, led to the identification of two alternatively spliced isoforms of the same gene. These isoforms, which lack the catalytic cysteine fundamental for enzymatic activity, showed widespread expression in neoplastic and normal tissues but were unstable at the protein level, being detectable, following transient transfection, only after lactacystin treatment to inhibit proteasomal degradation. Isoform-specific sequences which formed, respectively, as result of exon 1 splicing to either exon 3 or 4, encoded two distinct nonapeptides (AMAPIKTHL and AMAPIKVRL, not present in the full-length protein) with anchor residues for HLA-A2 and HLA-E molecules and able to stabilize HLA-A2 and HLA-E cell surface expression. HLA-E+ targets, loaded with these peptides, were not recognized by NK cells expressing CD94/NKG2A inhibitory or CD94/NKG2C activatory receptors. However, both peptides were recognized, although with low avidity, by HLA-E-restricted CD8+ CTL. The nonapeptide AMAPIKVRL was used to elicit HLA-A2-restricted CTL clones that killed peptide-pulsed lymphoblastoid cell lines and melanoma cells expressing the corresponding Prdx5 isoform. Our results suggest that alternatively spliced isoforms of Prdx5, through the generation of HLA-E- and HLA-A2-restricted peptides may be part of immune-mediated stress response contributing to the detection and elimination of damaged normal or neoplastic cells.
- Subjects :
- Alternative Splicing
Amino Acid Motifs immunology
Antigens, Neoplasm genetics
Antigens, Neoplasm immunology
Antioxidants metabolism
Catalytic Domain
Cell Line, Tumor
Clone Cells
Cysteine deficiency
Humans
Immunity, Cellular
Killer Cells, Natural metabolism
Melanoma genetics
Melanoma metabolism
Oxidative Stress immunology
Peptides chemistry
Peptides immunology
Peptides metabolism
Peroxiredoxins genetics
Peroxiredoxins immunology
Protein Binding
Protein Isoforms genetics
Protein Isoforms immunology
Protein Stability drug effects
Sequence Deletion
T-Lymphocytes, Cytotoxic immunology
T-Lymphocytes, Cytotoxic metabolism
HLA-E Antigens
Antigens, Neoplasm metabolism
HLA Antigens metabolism
HLA-A2 Antigen metabolism
Histocompatibility Antigens Class I metabolism
Killer Cells, Natural immunology
Melanoma immunology
Peroxiredoxins metabolism
Protein Isoforms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2377
- Volume :
- 21
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- International immunology
- Publication Type :
- Academic Journal
- Accession number :
- 19181932
- Full Text :
- https://doi.org/10.1093/intimm/dxn141