Genetic susceptibility to type 1 diabetes in the intracellular pathway of antigen processing - a subject review and cross-study comparison

Abstract

Ligand binding grooves of MHC class I molecules are able to load a panel of endogenous peptides of varying length and sequence derived from self or foreign origin to activate or deactivate cytotoxic CD8(+) T cells. Peptides are assembled with class I molecules by pathways that are either dependent or independent of transport by ABC proteins (TAP) and degradation in the immunoproteasome by its subunits LMP2 and LMP7. Those peptides that require TAP and LMP treatment appear to be subject to control and optimization by TAP for proper customizing and efficient presentation. Therefore, allelic variations in the coding sequences of TAP and LMP were suspected for a long time to be responsible for improper antigen processing, interruption of self-peptide presentation and reduced cell surface expression of MHC class I molecules resulting in the activation of autoreactive CD8(+) T cells. In this article we reviewed the controversial findings regarding the role of TAP and LMP genes in autoimmune diabetes and reevaluated data of eleven separate studies in a cross-study analysis by genotype and HLA haplotype matching. We could confirm previous results by showing that TAP2*651-A/F and TAP2*687-A/A are significantly associated with disease, independently of linkage disequilibrium (LD). LMP2-R/H surprisingly seems to be primarily disease-conferring although a weak association with DR4 serotypes can be observed. Our analysis also suggests that LMP7-B/B, TAP1-A/A and TAP2*687-A/B are the protective genotypes and that these associations are not secondary to LD with DRB1. Consequently, intracellular antigen processing associated with TAP- and proteasome-dependent pathways seems to be a critical element in T cell selection for the retention of a balanced immunity.

Figure 1

Recognition of an antigen presenting cell (big) by a CD8⁺ T cell (small) via interaction between TCR and MHC class I antigen epitope.

Figure 2. MHC class II gene region

The map shows genes which are relevant in the etiology of T1DM. Positions of TAP and LMP genes were determined in several studies by amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) [41, 72]. TAP and LMP genes are centromeric in the MHC class II region to DPA1 and DOB.

Figure 3. Crystal structures of the proteasome 20S surface

The images represent the crystal structures of 20S proteasome surfaces. Cleavage of peptides takes place at active sites of the β-subunits after acidic (peptidylglutamyl peptide hydrolyzing (PGPH) activity in β1), basic (trypsin-like activity in β2), and hydrophobic (chymotrypsin-like activity in β5) residues. Each image shows the nucleophilic Th1 in sticks, the basic residues in blue, the acidic residues in red, and the hydrophobic residues in white. Image courtesy by Olivier Coux, CRBM-CNRS, France.