Insights into the processing of MHC class I ligands gained from the study of human tumor epitopes

Abstract

The molecular definition of tumor antigens recognized by cytolytic T lymphocytes (CTL) started in the late 1980s, at a time when the MHC class I antigen processing field was in its infancy. Born together, these two fields of science evolved together and provided each other with critical insights. Over the years, stimulated by the potential interest of tumor antigens for cancer immunotherapy, scientists have identified and characterized numerous antigens recognized by CTL on human tumors. These studies have provided a wealth of information relevant to the mode of production of antigenic peptides presented by MHC class I molecules. A number of tumor antigenic peptides were found to result from unusual mechanisms occurring at the level of transcription, translation or processing. Although many of these mechanisms occur in the cell at very low level, they are relevant to the immune system as they determine the killing of tumor cells by CTL, which are sensitive to low levels of peptide/MHC complexes. Moreover, these unusual mechanisms were found to occur not only in tumor cells but also in normal cells. Thereby, the study of tumor antigens has illuminated many aspects of MHC class I processing. We review here those insights into the MHC I antigen processing pathway that result from the characterization of human tumor antigens recognized by CTL.

What shall we do with the damaged proteins in lung disease? Ask the proteasome!

“…In contrast, nonself antigenic peptides are recognised by activated CD8-positive T-cells and trigger a cytotoxic T-cell-mediated lysis of those cells that are brand-marked with nonself antigenic MHC I peptides. Activation of MHC I-dependent cytotoxic T-cell lysis thus provides an efficient surveillance mechanism for the detection of any cell bearing abnormal genes or proteins, as seen in response to viral infections, tumour antigens and rejection of transplants [32][33][34]. There is also some evidence that posttranslational modifications of antigenic peptides, such as phosphopeptides, add to the complexity of MHC I-mediated immune responses [35,36].…”

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

“…the first identified endogenous substrate of DPP9 was the tumor-related epitope RU1 [34][35][36][37][38][39][40][41][42] . Its hydrolysis by DPP9 results in its limited presentation on MhC class I molecules to the immune system linking DPP9 to the MhC class I antigen presentation pathway [28][29][30].…”

A Spliced Antigenic Peptide Comprising a Single Spliced Amino Acid Is Produced in the Proteasome by Reverse Splicing of a Longer Peptide Fragment followed by Trimming

“…Such peptides were found to arise from pseudogenes (17), from aberrant transcription of intronic or reverse-strand sequences (18,19), and from the translation of alternative open-reading frames (20) or posttranslational modifications such as threonine/serine phosphorylation (21) or asparagine deamidation (22,23) [reviewed in (2)]. More recently, we and others described peptides composed of two noncontiguous fragments of a protein that are bound together after the excision of their intervening segment.…”