KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C

Abstract

Human killer cell immunoglobulin-like receptors (KIRs) are distinguished by expansion of activating KIR2DS, whose ligands and functions remain poorly understood. The oldest, most prevalent KIR2DS is KIR2DS4, which is represented by a variable balance between “full-length” and “deleted” forms. We find that full-length 2DS4 is a human histocompatibility leukocyte antigen (HLA) class I receptor that binds specifically to subsets of C1+ and C2+ HLA-C and to HLA-A*11, whereas deleted 2DS4 is nonfunctional. Activation of 2DS4+ NKL cells was achieved with A*1102 as ligand, which differs from A*1101 by unique substitution of lysine 19 for glutamate, but not with A*1101 or HLA-C. Distinguishing KIR2DS4 from other KIR2DS is the proline–valine motif at positions 71–72, which is shared with KIR3DL2 and was introduced by gene conversion before separation of the human and chimpanzee lineages. Site-directed swap mutagenesis shows that these two residues are largely responsible for the unique HLA class I specificity of KIR2DS4. Determination of the crystallographic structure of KIR2DS4 shows two major differences from KIR2DL: displacement of contact loop L2 and altered bonding potential because of the substitutions at positions 71 and 72. Correlation between the worldwide distributions of functional KIR2DS4 and HLA-A*11 points to the physiological importance of their mutual interaction.

Human Cytomegalovirus Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in Patients Transplanted with NKG2C−/− Umbilical Cord Blood

“…However, differently from the murine model, the nature of the putative viral ligands recognized by NKG2C has yet to be identified. This holds true also for the viral ligands that might be recognized by the activating KIRs, whereas the specificity of these receptors for HLA class I molecules has been deciphered only for KIR2DS1 and KIR2DS4 (6)(7)(8). In this context, NK cells expressing KIR2DS1 (specific for HLA-C2) detected in patients A and C were derived from an HLA C1/C1 homozygous donor.…”

“…Alternatively, activating KIRs interact with DAP-12, an adaptor signaling molecule carrying an ITAM that can induce NK cell activation (6). So far, the HLA class I specificity of activating KIRs has been clearly demonstrated only for KIR2DS1 and KIR2DS4 (6)(7)(8). KIR genes are located on chromosome 19 and are inherited as haplotypes.…”

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

“…The binding motifs are referred to as C1 and C2 in HLA ‐C and Bw4 in HLA ‐B and HLA ‐A. The precise KIR binding motif of HLA ‐A*11, which can be recognized by KIR 2 DS 2, KIR 2 DS 4 and KIR 3 DL 2, has not been determined 10, 11. Interactions may also be sensitive to polymorphism outside the HLA and KIR binding motifs and to the presented peptide sequence.…”

α3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells

“…Both KIR and HLA are highly polymorphic, and recognition of the two molecules is specific (e.g., KIR3DL2 combines with HLA-A03 and HLA-A11) (10,13). Studies have shown that KIR3DL2 is a highly polymorphic framework gene with 86 allelic variants (47,48).…”

“…KIR2D interacts with HLA-C allotypes, whereas KIR3D interacts with HLA-B molecules, which display the Bw4 epitope, or with HLA-A. KIR3DL2 is a framework gene present in all humans, which plays a pivotal role in the modulation of NK-cell function (10)(11)(12). HLA-A11 interacts with KIR3DL2 to protect target cells from lysis by NK cells (13,14), and KIR3DL2 binding to HLA-B27 is crucial to the control of HIV progression (15,16).…”