Current Proteomics, 2009, 6, 13-24 13 1570-1646/09 $55.00+.00 ©2009 Bentham Science Publishers Ltd. Cellular Mechanisms that Edit the Immunopeptidome Dimitra Georgiadou and Efstratios Stratikos * Protein Chemistry Laboratory, Institute of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research “Demokritos”, Aghia Paraskevi, 15310, Greece Abstract: The adaptive immune response relies on the ability of T-lymphocytes to recognize small antigenic peptides pre- sented on the cell surface by specialized receptors of the Major Histocompatibility Complex (MHC). These peptides are either generated by the degradation of intracellular proteins (MHC class I pathway) or by the degradation of internalized extracellular proteins (MHC class II pathway and cross-presentation pathway). The number of proteins that can be degraded by these pathways runs to the thousands leading to a staggering number of possible peptide fragments. A small subset of these peptides is selected by the cell’s processing and presentation mechanisms to be presented on the cell sur- face by MHC molecules and has been defined as the immunopeptidome. The peptide sequences that comprise the im- munopeptidome control the immune response and variations of this peptide repertoire are key to understanding the host’s ability to fight pathogens, immune response to cancer as well as predisposition to autoimmunity and allergies. In the last few years it has been established that the composition of the immunopeptidome is regulated by specific cellular mecha- nisms that influence qualitative and quantitative aspects of the cellular immune response in a process that has been de- scribed as antigenic peptide editing. This review explores the current knowledge on these cellular mechanisms and dis- cusses the parallels between editing the MHC class I and class II immunopeptidomes. THE IMMUNOPEPTIDOME One of the biggest challenges of both the innate and adaptive immune systems is to correctly recognize pathogens and discriminate abnormal cells from their normal healthy counterparts. ‘Self’ versus ‘non-self’ discrimination, as pos- tulated by Janeway and colleagues in the early 90s, forms the integral basis for immune recognition and also dictates the proper activation of antigen-specific, humoral or cellular immune responses (Janeway, 1992) . Failure to do so can lead to defective immune responses towards pathogens. On the other hand, faulty recognition of healthy cells as diseased can lead to autoimmunity. Central to the correct recognition of abnormal cells is the presentation of small protein frag- ments (i.e. peptides) on the cell surface of every somatic cell. These peptides are presented bound onto specialized recep- tors called the Major Histocompatibility Complex (MHC) molecules. MHC molecules are loaded with peptides that are generated inside the cell by proteolysis of either intracellular proteins or endocytosed extracellular proteins. In that con- text, the protein content of a human cell, as well as that of its surrounding, is continually sampled and presented on the cell surface. Specialized immune system cells called T-lympho- cytes patrol the body and continually “sense” the peptides presented on the surface of other cells through direct molecu- lar interactions between specialized receptors on their plasma membrane (T-cell receptors, TCR) and the MHC-peptide complexes (Krogsgaard and Davis, 2005; Andersen et al., 2006; van der Merwe and Davis, 2003; Marrack et al., 2008). Successful recognition of peptide-MHC complexes on the cell surface signifies the presence of a pathogen inside or *Address correspondence to this author at the Protein Chemistry Labora- tory, Institute of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research “Demokritos”, Aghia Paraskevi, 15310, Greece; E-mail: stratos@rrp.demokritos.gr near the cell or some other sort of aberrant cell transforma- tion (i.e. cancer). This event, provokes a cascade of cellular processes in the T-lymphocyte that can lead to the lysis of the recognized cell, cytokine release and coordination of specific antibody synthesis (Dennert, 1997; Atkinson and Bleackley, 1995; MacPherson et al., 1999; Del Prete, 1998). Each cell contains several thousands of different protein molecules and an equally large number can be endocytosed from the cell’s surroundings. Each protein can be cleaved to tens or hundreds of different peptides by the cell’s prote- olytic machinery. These events lead to a staggering number of possible peptides that can be potentially used for presenta- tion. Each cell however, contains MHC molecules that have peptide-binding specificities that restrict which of these pep- tides can form stable MHC-peptide complexes and will be presented on the cell surface. Still, even after MHC binding restrictions, up to several thousands of peptides can be pre- sented on the cell surface. This collection of peptides has been called the immunopeptidome or the immunome and de- fines the immune system’s surveillance toolkit (Ortutay and Vihinen, 2006; Peters et al., 2005; Zhang et al., 2008; Ram- mensee et al., 1999; Schuler et al., 2007). During the recent years, it has gradually become evident that the immunopeptidome is not just generated by stochastic proteolytic processes but mechanisms exist that modulate its composition towards directions that are still unclear and can vary from individual to individual. This review will attempt to present current knowledge on the cellular mechanisms responsible for the generation and editing of the immunopep- tidome. Detailed understanding on how the immunopepti- dome is generated and edited can enable the prediction of antigenic epitopes as well as the rational design of immune response interventions for diseases varying from autoimmu- nity to cancer.