Special Issue: Immunopeptidomics
Coordinating Editors: Pierre Thibault and Claude Perreault (guest)
Fifty years have passed since the study of Benacerraf and McDevitt describing the exquisite regulation of the immune response by the major histocompatibility complex (MHC). The landmark discovery that T cell activation requires co-recognition of peptide antigens and self-MHC molecules revealed not only a unique receptor-ligand interaction but also a delicate balance between autoimmune response and effective protection against infection. These seminal studies laid the foundation to our current understanding of how immune cells distinguish between self and nonself.
T cells display a remarkable selectivity and discriminate self and nonself from an astonishing number of antigen peptides presented by MHC molecules, a property that is largely defined during their development in the thymus. Furthermore, the MHC locus is the most polymorphic region of the human genome and this structural diversity enables MHC molecules to present a wide distribution of peptide antigens originating from the degradation of endogenous (MHC Class I) or exogenous (MHC Class II) proteins. The biogenesis of peptide antigens is an intricate process shaped not only by environmental stimuli but also by specific proteolytic enzymes located in distinct organelles. The antigen repertoire, collectively referred to as the immunopeptidome, cannot be inferred from transcript or protein abundance, and mainly relies on mass spectrometry analyses of peptides eluted from MHC complex. However, mass spectrometry alone is not sufficient to unveil the full repertoire of antigens concealed by MHC molecules. Indeed, structural variants arising from genomic polymorphisms or non canonical regions of the genome are absent from the reference proteomes and their discovery requires more elaborated databases that leverage proteogenomic search strategies. Recent technological advances in MHC isolation methods, mass spectrometry sensitivity and novel database search approaches have fueled immunopeptidomic discoveries and open up new perspectives for cancer immunotherapy. It is in this context that we assembled experts and opinion leaders in immunopeptidomics to contribute to this special issue and share their findings and views of this blossoming field of research.
Artistic rendition of antigen presentation by the major histocompatibility complex class I molecules’. Credit: Luciana Giono.