|M.Sc Student||Hendler Ayellet|
|Subject||Modulation of the Cellular Proteome and HLA Peptidome by|
|Department||Department of Biology||Supervisor||Professor Emeritus Arie Admon|
|Full Thesis text|
Interferon-γ (IFN-γ) is a central cytokine of the immune response and is widely known for its pleiotropic activity on cellular processes in cancer cells. IFN-γ has the special ability to induce cells to over-express their cells’ surface antigens on key recognition molecules of the immune system-the Human Leukocyte Antigens (HLA). The HLA molecules are divided into two general classes: HLA class I molecules are expressed on nucleated cells in varying amounts and present peptides to cytotoxic T cells. HLA class II molecules are presented mostly by professional antigen-presenting cells (APCs) to helper T cells to alert them to the presence of foreign proteins or pathogens in the body. The peptides displayed within the context of the HLA molecules (the ‘HLA peptidome’) represent the degradation products of cellular proteins.
In this study, we aimed to improve our understanding of how IFN-γ modulates in epithelial cancer cells both the HLA peptidome and the proteome.
Initially, using FACS and confocal microscopy analyses, we demonstrated that IFN-γ clearly up-regulated the HLA presentation. Furthermore, the gathered data indicated that IFN-γ treatment managed to alter the repertoires of the presented HLA class I and class II peptides. These INF-γ induced HLA peptides are of significant biological interest within the association with IFN-γ and their potential use as IFN-γ induced vaccine candidates.
This group of INF-γ induced HLA peptides included peptides derived from intracellular transport vesicles proteins, suggesting that part of the major influence of IFN-γ on HLA presentation may involve a switch to the peptide processing for presentation by macroautophagy on top of the switch to the immunoproteasome. We also suggest the involvement of INF-γ with enhanced presentation of peptides derived from lipogenic enzymes in cancer cells. Eventually, the identification of shared source proteins and overlapping peptides of HLA class I and class II peptides, observed in our study, can suggest that shared processing pathways should be present in cells. Furthermore, since we know that the class II peptidome is mostly generated within the lysosome-like organelle, it should mean that also the class I peptidome could be generated in the same compartment.
The proteomics and the HLA peptidome data, gathered in this study, provide a new understanding of the effects IFN-γ exerts at the cellular level. The results not only corroborate earlier works in the field of INF-γ, but also suggest additional proteins to be involved in the cellular response to this cytokine.