Know thy immune self and non-self: Proteomics informs on the expanse of self and non-self, and how and where they arise

Abstract

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) restri ction. 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. Insight into the precise composition and biology of self and non-self immunopeptidomes is 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 revolutionised the field.

Keywords: T cell epitope; antigen presentation; antigen processing; human leukocyte antigen; immunopeptidomics; major histocompatibility complex; mass spectrometry.

FIGURE 1

A schematic rendition of MHC‐I biosynthesis and assembly with peptide cargoes. The assembly of MHC‐I molecules begins with the co‐translational insertion of the heavy chain into the lumen of the endoplasmic reticulum (ER). Herein the nascent heavy chain binds to the ER chaperone calnexin to facilitate initial folding and assembly with β2‐microglobulin (β2m). This unstable heterodimer is stabilized by binding to a related ER chaperone calreticulin. This interaction makes the complex receptive to the peptide loading complex (PLC). This association with the PLC stabilizes the empty heterodimer such that the antigen‐binding groove adopts and maintains a conformation receptive to peptide loading. The PLC—consisting of the heavy chain‐β2m heterodimer, calreticulin, tapasin, and the ER‐resident thiol‐oxidoreductase/disulphide isomerase ERp57—facilitates peptide binding to the heterodimer. Initial peptide‐bound MHC‐I undergoes architectural editing via tapasin in the PLC to ensure high‐affinity peptide (p)/MHC‐I complex formation prior to exiting the ER. TAP‐binding protein related (TAPBPR), independent of the PLC, edits for high‐affinity peptide binding to MHC‐I in a poorly understood mechanism. Peptides generated in the cytosol—the sources of which and their production are explained in the text—are made available for pMHC‐I assembly in the ER lumen by transporter associated with antigen processing (TAP)‐1 and TAP‐2. Many of the peptides that are delivered into the ER are longer than the preferred 8–10 residues; these undergo further trimming by ER aminopeptidases, human ERAP1 (mouse ERAAP) and/or human ERAP2. Finally, high‐affinity pMHC‐I complexes are released from the PLC, which then falls apart into constituent parts, available for the next round of pMHC‐I assembly. Perhaps to make the process efficient, in addition to peptide translocation from the cytosol to the ER lumen, TAP‐1 and TAP‐2 heterodimer forms a scaffold that tethers two PLCs into a complex. pMHC‐I released from the PLC quickly egresses from the ER, and negotiates the Golgi apparatus en route to the cell surface for an appraisal by CD8⁺ T cells