Know Thy Immune Self & Non-Self: Proteomics informs on the expanse of self and non-self, and how and where they arise

T cells play an important role in the adaptive immune response to a variety of infections and cancers. Initiation of a T cell mediated immune response requires antigen recognition in a process termed MHC (Major Histocompatibility Complex) restriction. A T cell antigen is a composite structure made up of a peptide fragment bound within the antigen-binding groove of an MHC-encoded class I or class II molecule. Insights into the precise composition and biology of self and non-self immunopeptidomes are essential to harness T cell mediated immunity to prevent, treat, or cure infectious diseases and cancers. T cell antigen discovery is an arduous task! The pioneering work in the early 1990s has made large-scale T cell antigen discovery possible. Thus, advancements in mass spectrometry coupled with proteomics and genomics technologies make possible T cell antigen discovery with ease, accuracy, and sensitivity. Yet we have only begun to understand the breadth and the depth of self and non-self immunopeptidomes because the molecular biology of the cell continues to surprise us with new secrets directly related to the source, and the processing and presentation of MHC ligands. Focused on MHC class I molecules, this review, therefore, provides a brief historic account of T cell antigen discovery and, against a backdrop of key advances in molecular cell biologic processes, elaborates on how proteogenomics approaches have revolutionized the field.