HLA-E: a novel player for histocompatibility

Abstract

The classical class I human leukocyte antigens (HLA-A, -B, and -C) present allele-specific self- or pathogenic peptides originated by intracellular processing to CD8(+) immune effector cells. Even a single mismatch in the heavy chain (hc) of an HLA class I molecule can impact on the peptide binding profile. Since HLA class I molecules are highly polymorphic and most of their polymorphisms affect the peptide binding region (PBR), it becomes obvious that systematic HLA matching is crucial in determining the outcome of transplantation. The opposite holds true for the nonclassical HLA class I molecule HLA-E. HLA-E polymorphism is restricted to two functional versions and is thought to present a limited set of highly conserved peptides derived from class I leader sequences. However, HLA-E appears to be a ligand for the innate and adaptive immune system, where the immunological response to peptide-HLA-E complexes is dictated through the sequence of the bound peptide. Structural investigations clearly demonstrate how subtle amino acid differences impact the strength and response of the cognate CD94/NKG2 or T cell receptor.

Figure 1

C-terminal peptide residues mediate contact between the HLA-E^VMAPRTLFL complex and the CD94/NKG2A receptor. This structure represents the interactions between the CD94/NKG2A receptor and the HLA-E^VMAPRTLFL complex (PDB: 3CDG) [4]. The CD94 subunit (raspberry) dominates the recognition of the peptide (orange sticks) with several contacts including hydrogen bonds of Ser110 to the peptide's p5-Arg and Gln112 to p6-Thr. The peptide's p8-Phe is surrounded by a polar pocket created by Asn156, Asn158, and Asn160 and van der Waals contacts with Phe114. p5-Arg also builds a salt bridge to Glu152 of the HLA-E heavy chain (pale teal) that may prevent more charged interactions with CD94/NKG2A. Residue Pro171 of NKG2A (pale grey) interacts with p5-Arg by van der Waals interactions. Hydrogen bonds are represented as black dashed lines, and salt bridges are given in blue.