Immune recognition of a human renal cancer antigen through post-translational protein splicing.
Cytotoxic T lymphocytes (CTLs) detect and destroy cells displaying class I molecules of the major histocompatibility complex (MHC) that present oligopeptides derived from aberrant self or foreign proteins. Most class I peptide ligands are created from proteins that are degraded by proteasomes and transported, by the transporter associated with antigen processing, from the cytosol into the endoplasmic reticulum, where peptides bind MHC class I molecules and are conveyed to the cell surface. C2 CTLs, cloned from human CTLs infiltrating a renal cell carcinoma, kill cancer cells overexpressing fibroblast growth factor-5 (FGF-5). Here we show that C2 cells recognize human leukocyte antigen-A3 MHC class I molecules presenting a nine-residue FGF-5 peptide generated by protein splicing. This process, previously described strictly in plants and unicellular organisms, entails post-translational excision of a polypeptide segment followed by ligation of the newly liberated carboxy-terminal and amino-terminal residues. The occurrence of protein splicing in vertebrates has important implications for the complexity of the vertebrate proteome and for the immune recognition of self and foreign peptides.
Hanada
Ken-Ichi
K
Surgery Branch, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building10, Room 2B42, Bethesda, Maryland 20892, USA. khanada@nih.gov
Yewdell
Jonathan W
JW
Yang
James C
JC
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D019556:COS Cells; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015791:HLA-A3 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007680:Kidney Neoplasms / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D019154:Protein Splicing; D012326:RNA Splicing; D012270:Ribosomes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; C496449:FGF5 protein, human; D015791:HLA-A3 Antigen; D051521:Fibroblast Growth Factor 5; D005346:Fibroblast Growth Factors