MHC class II epitope predictive algorithms

Abstract

Major histocompatibility complex class II (MHC-II) molecules sample peptides from the extracellular space, allowing the immune system to detect the presence of foreign microbes from this compartment. To be able to predict the immune response to given pathogens, a number of methods have been developed to predict peptide-MHC binding. However, few methods other than the pioneering TEPITOPE/ProPred method have been developed for MHC-II. Despite recent progress in method development, the predictive performance for MHC-II remains significantly lower than what can be obtained for MHC-I. One reason for this is that the MHC-II molecule is open at both ends allowing binding of peptides extending out of the groove. The binding core of MHC-II-bound peptides is therefore not known a priori and the binding motif is hence not readily discernible. Recent progress has been obtained by including the flanking residues in the predictions. All attempts to make ab initio predictions based on protein structure have failed to reach predictive performances similar to those that can be obtained by data-driven methods. Thousands of different MHC-II alleles exist in humans. Recently developed pan-specific methods have been able to make reasonably accurate predictions for alleles that were not included in the training data. These methods can be used to define supertypes (clusters) of MHC-II alleles where alleles within each supertype have similar binding specificities. Furthermore, the pan-specific methods have been used to make a graphical atlas such as the MHCMotifviewer, which allows for visual comparison of specificities of different alleles.

Figure 1

The major histocompatibility complex (MHC) class II antigen presentation pathway. Specialized antigen-presenting cells ingest exogenous antigens into endosomes by endocytosis or phagocytosis. The endosomes fuse with MHC class II containing lysosomes. The antigens (and MHC class II invariant chain) are degraded into peptides by proteases, and the release of the CLIP peptide allows the MHC class II molecule to bind antigen peptides before migration to the plasma membrane.

Figure 2

Protein crystal structure of major histocompatibility complex (MHC) class II molecule (HLA-DRB1*0101) in complex with peptide (PDB id: 1AQD). The MHC α-chain is shown in dark-blue, and the β-chain in light blue. The peptide (GSDWRFLRGYHQYA) is shown in red/pink, with the peptide-binding core (WRFLRGYHQ) in red, and the peptide-flanking amino acids in pink.

Figure 3

Sequence logo representation of the binding motif for two HLA-DR molecules. The Kullback–Leibler (KL) sequence logo is taken from the MHC Motif Viewer website. Left: HLA-DRB1*0301, Right: HLA-DRB1*1501. The KL information content is plotted along the nine-mer binding core (solid blue line). Amino acids with positive influence on the binding are plotted on the positive y-axis, and amino acids with a negative influence on binding are plotted on the negative y-axis. The height of each amino acid is given by their relative contribution to the binding specificity (for details see ref. 73). The primary anchor positions (P1, P4, P6 and P9) show clear and distinct amino acid preferences. At P1, both molecules prefer hydrophobic amino acids. HLA-DRB1*0301 has a preference for aspartic acid at P4 whereas at P6 and P9 basic amino acids are preferred. HLA-DRB1*1501, on the other hand, prefers hydrophobic and neutral amino acids at the P4 and P6 anchors.