Characterization of the peptide binding specificity of the HLA class I alleles B*38:01 and B*39:06

Abstract

B*38:01 and B*39:06 are present with phenotypic frequencies <2% in the general population, but are of interest as B*39:06 is the B allele most associated with type 1 diabetes susceptibility and 38:01 is most protective. A previous study derived putative main anchor motifs for both alleles based on peptide elution data. The present study has utilized panels of single amino acid substitution peptide libraries to derive detailed quantitative motifs accounting for both primary and secondary influences on peptide binding. From these analyses, both alleles were confirmed to utilize the canonical position 2/C-terminus main anchor spacing. B*38:01 preferentially bound peptides with the positively charged or polar residues H, R, and Q in position 2 and the large hydrophobic residues I, F, L, W, and M at the C-terminus. B*39:06 had a similar preference for R in position 2, but also well-tolerated M, Q, and K. A more dramatic contrast between the two alleles was noted at the C-terminus, where the specificity of B*39:06 was clearly for small residues, with A as most preferred, followed by G, V, S, T, and I. Detailed position-by-position and residue-by-residue coefficient values were generated from the panels to provide detailed quantitative B*38:01 and B*39:06 motifs. It is hoped that these detailed motifs will facilitate the identification of T cell epitopes recognized in the context of two class I alleles associated with dramatically different dispositions towards type 1 diabetes, offering potential avenues for the investigation of the role of CD8 T cells in this disease.

Keywords: Antigen presentation; Epitopes; Major histocompatibility complex; Type 1 diabetes.

Figure 1. Summary B*38:01 and B*39:06 peptide binding motifs

The peptide binding motifs of B*38:01 (upper panel) and B*39:01 (lower panel), determined using panels of single amino acid substituted peptides as described in the text, are summarized to show the main (red fill) and secondary (blue fill) anchor positions. The most preferred residues at the primary anchor positions are indicated by enlarged font. Tolerated anchor residues are also shown. The most preferred residues at secondary anchor positions are as highlighted in the text.