Killer cell immunoglobulin-like receptor 3DL1-mediated recognition of human leukocyte antigen B

Abstract

Members of the Killer Immunoglobulin-Like Receptor (KIR) family, a large group of polymorphic receptors expressed on Natural Killer (NK) cells, recognise particular peptide-laden Human Leukocyte Antigen (pHLA) class I molecules and play a pivotal role in innate immune responses1. Allelic variation and extensive polymorphism within the three-domain KIR family (KIR3D, domains D0–D1–D2) affects pHLA binding specificity and is linked to the control of viral replication and the treatment outcome of certain haematological malignancies1–3. We describe the structure of the KIR3DL1 receptor, bound to HLA-B*5701 complexed with a self-peptide. KIR3DL1 clamped around the C-terminal end of the HLA-B*5701 antigen (Ag)-binding cleft, resulting in two discontinuous footprints on the pHLA. Firstly, the D0 domain, a distinguishing feature of the KIR3D family, extended towards β2-microglobulin and abutted a region of the HLA molecule that exhibited limited polymorphism, thereby acting as an “innate HLA sensor” domain. Secondly, while the D2-HLA-B*5701 interface exhibited a high degree of complementarity, the D1-pHLA-B*5701 contacts were sub-optimal and accommodated a degree of sequence variation both within the peptide and the polymorphic region of the HLA molecule. While the two-domain KIR (KIR2D) and KIR3DL1 docked similarly onto HLA-C4,5 and HLA-B respectively, the corresponding D1-mediated interactions differed markedly, thereby providing insight into the specificity of KIR3DL1 for discrete HLA-A and HLA-B allotypes. Collectively, in association with extensive mutagenesis studies at the KIR3DL1-pHLA B*5701 interface, we provide a framework for understanding the intricate interplay between peptide variability, KIR3D and HLA polymorphism in determining the specificity requirements of this essential innate interaction that is conserved across primate species.

Host-Specific Adaptation of HIV-1 Subtype B in the Japanese Population

“…Another possibility is selection by NK cells, as KIR may recognize sites outside the peptidebinding groove. Indeed, KIR3DL1 binds to the loop including position 91 of HLA-B*57:01 (44). However, it is not clear whether KIR2DLs, which are receptors for HLA-C, can bind to the loop outside the peptide-binding groove of HLA-C molecules.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…3). Even a single nucleotide mutation can dramatically change receptor expression,25, 31, 32, 33 ligand specificity34, 35, 36 or signalling strength. KIR gene copy number variation influences NK cell education, shaping the NK cell repertoire 37.…”

“…A synergy of population genetics, phylogenetic analysis and comparison of nucleotide substitution rates among codons showed that this diversity is focused towards the parts of the KIR molecule that bind the HLA class I and peptide 61. The prediction that these major lineages of KIR3DL1/S1 have distinct ligand HLA/peptide‐binding properties has been borne out with crystallographic and functional studies 35, 39, 41, 42, 62, 63, 64, 65. Expansion of the phylogenetic analyses to include other KIR molecules revealed natural selection has consistently been focused towards residues that affect interaction with the HLA class I ligand,66 as well as those that affect the signalling properties of the receptor 67…”

“…Three key advancements have progressed understanding of the recognition of HLA class I by KIR; (i) the crystal structures of KIR in complex with their HLA class I ligands,10, 35, 70, 99 (ii) the development of soluble KIR36, 100, 101 and (iii) their use in a multiplex immunoassay against a broad panel of HLA class I allotypes102, 103 (Fig. 3).…”

“…1). 35, 114, 115 Recognition of Bw4 by KIR3DL1 is sensitive to polymorphism both within and outside the Bw4 motif, as well as to the sequence of the bound peptide 42, 63, 116, 117, 118. Early work showed that HLA‐Bw4 allotypes with I80 formed more potent ligands for KIR3DL1 than those with T80,119 a functional difference reinforced by associations with disease outcome 27, 58, 120, 121, 122.…”