Understanding the genesis of the spliced immunopeptidome

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Presentation of antigens by major histocompatibility complex (MHC) molecules is a vital process in the life of an organism. Thousands of such antigens are presented on the surface of virtually all cells in our body. Those antigens are protein fragments (or peptides) that are generated following degradation of proteins inside the cell. Collectively, this ocean of peptides is referred to as the immunopeptidome and can be characterized using advanced technologies. Until now, mass spectrometry (MS) technology is the method of choice for the analysis of the immunopeptidome. The current dogma in antigen presentation is that immune T cells can recognize peptides that are encoded by the genome. Unexpectedly, two landmark studies provided evidences that a significant proportion of the immunopeptidome, in human cells, is composed of peptides that are not encoded in the genome. They may be the result of a very poorly understood mechanism referred to as peptide splicing. The potential implications of the presence of spliced peptides for all facets of the immune system biology is very significant, because their presence dramatically widens the repertoire of antigenic peptides presented to the immune system. However, deciphering the composition of the spliced immunopeptidome is very challenging. In fact, spliced peptides are completely unpredictable from genomic information and MS technologies represent so far the only approach to identify them on a global scale. To date, only a handful of researchers worldwide have developed the appropriate resources and expertise to analyse the spliced immunopeptidome. In our group, we recently found that a significant proportion of the immunopeptidome, analyzed in the mouse as model, is composed of such spliced peptides. These discoveries raise the important point that generation and presentation of spliced peptides is a conserved biological process across evolution. Are spliced peptides randomly generated? In fact, very little is known about their genesis. The objective of our research program is to test the hypothesis that genesis of the spliced immunopeptidome is systematically orchestrated by well-defined catalytic processes regulated at multiple levels inside the cell. First, we will investigate the global relationship between peptide splicing and protein conformational changes on a proteome-wide scale. Second, we will assess the contribution of the proteasome catalytic subunits to the global composition of the spliced immunopeptidome. Third, we will evaluate the role of autophagy and other proteases in catalyzing peptide splicing. The long-term objective of our NSERC program is to gain in-depth understanding of how spliced peptides are generated and presented by MHC molecules. This will allow us to predict them, and will ultimately enable the engineering of new biological systems to control their generation and function in immunity.