Cellular Mechanisms that Edit the Immunopeptidome

Abstract

The adaptive immune response relies on the ability of T-lymphocytes to recognize small antigenic peptides presented 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 surface by MHC molecules and has been defined as the immunopeptidome. The peptide sequences that comprise the immunopeptidome 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 mechanisms that influence qualitative and quantitative aspects of the cellular immune response in a process that has been described as antigenic peptide editing. This review explores the current knowledge on these cellular mechanisms and discusses the parallels between editing the MHC class I and class II immunopeptidomes.

Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides

“…The importance of antigenic peptide precursor trimming by aminopeptidases has emerged the last few years as both a necessary step for antigenic peptide generation but also as a novel paradigm of regulation of the adaptive immune response [17, 37]. However the discovery that three distinct aminopeptidases participate in antigen processing has raised important questions regarding the regulation of antigenic peptide generation that are far from answered.…”

The Crystal Structure of Human Endoplasmic Reticulum Aminopeptidase 2 Reveals the Atomic Basis for Distinct Roles in Antigen Processing

“…The best characterized of the two, ERAP1, has been shown to be required for the generation of many antigenic epitopes both in vitro and inside cells. , ERAP1 knockout mice were found to be deficient in the generation of many epitopes but also present an altered peptide repertoire on their surface, suggesting that ERAP1 epitope-mediated trimming can influence immunodominance. − Furthermore, ERAP1 is specialized for trimming relatively large peptides (10–16 amino acids long) while sparing short ones, a property that is consistent with its biological role in preparing peptides for MHCI binding. , Finally, ERAP1 can also destroy several antigenic epitopes by trimming them to lengths inappropriate for MHCI binding . This dual function of ERAP1 has led to its characterization as an antigenic peptide editor. , …”

“…6 This dual function of ERAP1 has led to its characterization as an antigenic peptide editor. 10,13 Given the enormous number of protein sequences that are sampled by the proteasomal antigen generation and processing pathway, ER-resident aminopeptidases are expected to process efficiently a very large number of different peptide sequences. ERAP1, however, has been shown to have preferences for peptide−substrate sequences, a property that may at least partially explain antigenic peptide selection but opens questions regarding the processing of many epitopes that are poorly trimmed by ERAP1.…”

Endoplasmic Reticulum Aminopeptidase 1 Is Involved in Anti-viral Immune Response of Hepatitis B Virus by Trimming Hepatitis B Core Antigen to Generate 9-Mers Peptides

“…However, the 8–9-mers enzymatic fragments of the increased peptide were not observed in untreated control. It will be useful to determine whether hyper-editing of the 15-mers peptide happened as a proportion of peptides that enter the ER are destroyed by ERAP1 to below the minimal size needed for presentation on MHC class I molecules ( Hammer et al, 2007 ; Georgiadou and Stratikos, 2009 ; Chen and Tian, 2019 ). Therefore, ERAP1 functions in a paradoxical manner as an interrupter limiting antigen presentation while it is still an ideal aminopeptidase to generate the final optimal length of peptides for pMHC I presentation ( York et al, 2002 ).…”