Peptides with dual binding specificity for HLA-A2 and HLA-E are encoded by alternatively spliced isoforms of the antioxidant enzyme peroxiredoxin 5

被引:25
作者
Sensi, Marialuisa [1 ]
Pietra, Gabriella [2 ]
Molla, Alessandra [1 ]
Nicolini, Gabriella [1 ]
Vegetti, Claudia [1 ]
Bersani, Ilaria [1 ]
Millo, Enrico [3 ,4 ]
Weiss, Elizabeth [5 ]
Moretta, Lorenzo [2 ,4 ,6 ]
Mingari, Maria Cristina [2 ,7 ]
Anichini, Andrea [1 ]
机构
[1] Ist Nazl Tumori, Dipartimento Oncol Sperimentale Immunobiol Tumori, Fdn IRCCS, I-20133 Milan, Italy
[2] Univ Genoa, Dipartimento Med Sperimentale, Sez Patol Gen, Genoa, Italy
[3] Univ Genoa, Dipartimento Med Sperimentale, Sez Biochim, Genoa, Italy
[4] Univ Genoa, Ctr Eccellenza Ric Biomed, Genoa, Italy
[5] Univ Munich, Inst Anthropol & Human Genet, D-8000 Munich, Germany
[6] Ist Giannina Gaslini, I-16148 Genoa, Italy
[7] Ist Nazl Ric Canc, I-16132 Genoa, Italy
关键词
splice variants; tumor antigen; MHC class Ia; MHC class Ib; HUMAN-MELANOMA; CUTTING EDGE; E EXPRESSION; CELLS; ANTIGEN; RECOGNITION; LIGAND; IDENTIFICATION; MELANOCYTES; CD94/NKG2A;
D O I
10.1093/intimm/dxn141
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:257 / 268
页数:12
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