Variations in MHC class I antigen presentation and immunopeptidome selection pathways

Abstract

Major histocompatibility class I (MHC-I) proteins mediate immunosurveillance against pathogens and cancers by presenting antigenic or mutated peptides to antigen receptors of CD8+ T cells and by engaging receptors of natural killer (NK) cells. In humans, MHC-I molecules are highly polymorphic. MHC-I variations permit the display of thousands of distinct peptides at the cell surface. Recent mass spectrometric studies have revealed unique and shared characteristics of the peptidomes of individual MHC-I variants. The cell surface expression of MHC-I-peptide complexes requires the functions of many intracellular assembly factors, including the transporter associated with antigen presentation (TAP), tapasin, calreticulin, ERp57, TAP-binding protein related (TAPBPR), endoplasmic reticulum aminopeptidases (ERAPs), and the proteasomes. Recent studies provide important insights into the structural features of these factors that govern MHC-I assembly as well as the mechanisms underlying peptide exchange. Conformational sensing of MHC-I molecules mediates the quality control of intracellular MHC-I assembly and contributes to immune recognition by CD8 at the cell surface. Recent studies also show that several MHC-I variants can follow unconventional assembly routes to the cell surface, conferring selective immune advantages that can be exploited for immunotherapy.

Keywords: HLA class I; MHC class I.

Figure 1.. Major histocompatibility class I (MHC-I) surface interactions and assembly.

( A) Crystal structure and cartoon representation of MHC-I (red: heavy chain, orange: β2m, yellow: peptide)/TCR (green) (PDB 5C07 ) on CD8 ⁺ T cells, MHC-I/CD8 co-receptor (cyan and magenta) (PDB 3DMM and PDB 3QZW ), or MHC-I/KIR3DL1 (blue) on natural killer (NK) cells (PDB 5B38 ). ( B) Cryo-EM structure of MHC-I in the PLC (yellow: calreticulin, blue: tapasin, purple: ERp57) (PDB 6ENY adapted from data freely accessible at: https://www.rcsb.org/structure/6ENY) or with TAPBPR (cyan) (PDB 5WER ) in the peptide-deficient form. Arrows highlight interactions between tapasin and MHC-I, calreticulin and the MHC-I glycan, calreticulin and tapasin, calreticulin and ERp57, and tapasin and Erp57. β2m, beta2-microglobulin; KIR, killer cell immunoglobulin-like receptor; PLC, peptide loading complex; TAPBPR, transporter associated with antigen presentation-binding protein related; TCR, T-cell receptor.

Figure 2.. Binding motifs of 9-mer peptides bound to select HLA-A, HLA-B, and HLA-C.

Seq2Logo motifs of eluted 9-mer peptides that bind to the specified HLA-A, HLA-B, and HLA-C allotypes grouped by supertype for HLA-A and HLA-B. All motifs are derived on the basis of analysis of eluted peptide sets (adapted from data freely accessible at: ftp://massive.ucsd.edu/MSV000084172/). Within a given supertype , the peptide motifs are similar. Many HLA-A allotypes lack the strong P2 restriction generally seen in HLA-B and HLA-C. The HLA-B*07 allotype binds to peptides that are disfavored by transporter associated with antigen presentation (TAP), and allotypes belonging to this supertype are expressed at low levels on the surface of lymphocytes but at higher levels on TAP-deficient cells . HLA, human leukocyte antigen.