Mechanism of Immune Peptide Presentation in Immunopeptidomics

Immunopeptidomics is a cutting-edge field that focuses on understanding the mechanisms of antigen presentation within the immune system, primarily by analyzing and identifying peptide fragments presented by Antigen-Presenting Cells (APCs). These peptides bind to Major Histocompatibility Complex (MHC) molecules and are displayed on the cell surface, initiating a specific immune response through T-cell recognition. Understanding the mechanism of immune peptide presentation is critical for advancing our knowledge of immune system functionality and providing theoretical support for cancer immunotherapy and vaccine development.

 

Generation and Degradation of Immune Peptides

The generation of immune peptides is mainly accomplished through protein degradation systems, involving two primary pathways: the proteasome and lysosome.

 

1. Proteasome Pathway

This pathway primarily handles intracellular antigen degradation. Intracellular proteins are first marked by ubiquitination and then degraded into short peptides by the 26S proteasome. These peptides are further processed in the cytosol and transported into the Endoplasmic Reticulum (ER) by the Transporter Associated with Antigen Processing (TAP), where they bind to MHC class I molecules to form stable MHC-I/peptide complexes, which are subsequently transported to the cell surface for CD8+ T cell recognition.

 

2. Lysosomal Pathway

This pathway is mainly involved in the processing of extracellular antigens. Extracellular antigens enter APCs via endocytosis, forming endosomes that fuse with lysosomes, where the antigens are degraded into short peptides. These peptides bind to MHC class II molecules within the endosome, forming MHC-II/peptide complexes, which are transported to the cell surface for CD4+ T cell recognition.

 

Structure of MHC Molecules and Peptide Binding

MHC molecules are highly polymorphic membrane proteins that can bind various antigenic peptides and present them to T cells.

 

1. MHC Class I Molecules

These consist of an alpha chain and a β2-microglobulin. The peptide-binding groove is formed by the α1 and α2 domains, accommodating peptides of 8-11 amino acids. The binding and stability of MHC-I/peptide complexes depend on interactions between the terminal residues of the peptide and the amino acid residues in the MHC-I binding groove.

 

2. MHC Class II Molecules

These consist of an alpha and a beta chain, with the peptide-binding groove formed by the α1 and β1 domains, allowing binding of longer peptides (13-25 amino acids). Unlike MHC-I, the MHC-II binding groove is open-ended, enabling peptides to extend beyond the groove.

 

Mechanism of Antigen Peptide Binding to MHC

The binding of antigenic peptides to MHC molecules is a critical step in immune peptide presentation, characterized by high selectivity and specificity.

 

1. Peptide Processing and Loading

In the MHC-I presentation pathway, peptides transported by TAP into the ER are further trimmed by ERAP (Endoplasmic Reticulum Aminopeptidase) to the optimal length for MHC-I binding. Peptide loading onto MHC-I occurs within the ER, facilitated by chaperones such as calnexin, calreticulin, and ERp57, which aid in MHC-I folding and peptide loading.

 

2. Peptide Loading Complex

The loading of peptides onto MHC-II occurs within endosomal compartments. When synthesized in the ER, MHC-II binds to an invariant chain (Ii), which occupies the peptide-binding groove, preventing premature peptide loading. The MHC-II/Ii complex travels through the Golgi apparatus to the endosome, where Ii is degraded, leaving a CLIP fragment that is subsequently displaced by HLA-DM, allowing the antigenic peptide to bind to MHC-II.

 

Regulatory Mechanisms of Immune Peptide Presentation

1. Regulation of TAP and Peptide Transport

The activity of TAP directly influences the efficiency of peptide transport in the MHC-I pathway. Cytokines like IFN-γ can upregulate TAP expression, enhancing antigen presentation. Conversely, certain viruses can downregulate TAP expression or inhibit its function to evade immune surveillance.

 

2. Role of HLA-DM in Peptide Selection

HLA-DM plays a crucial role in the MHC-II presentation pathway by promoting CLIP removal and facilitating high-affinity peptide loading onto MHC-II molecules. This process is negatively regulated by HLA-DO, modulating immune response strength under different physiological conditions.

 

The mechanism of immune peptide presentation plays a critical role in the immune system, ensuring the timely recognition and elimination of pathogens and abnormal cells. In-depth research into this mechanism offers insights into immune evasion by diseases and enables the development of effective therapeutic approaches, such as cancer vaccines and immune checkpoint inhibitors.