Resurrecting KIR2DP1: A Key Intermediate in the Evolution of Human Inhibitory NK Cell Receptors That Recognize HLA-C

Abstract

KIR2DP1 is an inactive member of the human lineage III KIR family, which includes all HLA-C specific receptors. The lethal, and only, defect in KIR2DP1 is a nucleotide deletion in codon 88. Fixed in modern humans, the deletion is also in archaic human genomes. KIR2DP1 is polymorphic, with dimorphism at specificity-determining position 44. By repairing the deletion, we resurrected eleven alleles of KIR2DP1F, the functional antecedent of KIR2DP1. We demonstrate how K44-KIR2DP1F with lysine 44 recognized C1+HLA-C, whereas T44-KIR2DP1F recognized C2+HLA-C. Dimorphisms at twelve other KIR2DP1F residues modulate receptor avidity or signaling. KIR2DP1 and KIR2DL1 are neighbors in the centromeric KIR region, and in tight linkage disequilibrium. Like KIR2DL1, KIR2DP1 contributed to CenA and CenB KIR haplotype differences. Encoded on CenA, C1-specific K44-KIR2DP1F were stronger receptors than the attenuated C2-specific T44-KIR2DP1F encoded on CenB. The last common ancestor of humans and chimpanzees had diverse lineage III KIR that passed on to chimpanzees, but not to humans. Early humans inherited activating KIR2DS4 and an inhibitory lineage III KIR, likely encoding a C1-specific receptor. The latter spawned the modern family of HLA-C receptors. KIR2DP1F has properties consistent with KIR2DP1F having been the founder gene. It first encoded only K44-C1 receptors, but then evolved T44-C2 receptors. The emergence of dedicated KIR2DL2/3 and KIR2DL1 genes encoding C1 and C2 receptors, respectively, could have led to obsolescence of KIR2DP1F. Alternatively, pathogen subversion led to its demise. Preservation of KIR2DP1F functional polymorphism appears a side effect of fixing the deletion in KIR2DP1F by micro gene conversion.

Missing or altered self: human NK cell receptors that recognize HLA-C

“…The latter gene subsequently became subject to a process of gene duplication and differentiation that spawned a family of six human-specific KIR genes and formation of the distinctive CenA and CenB KIR haplotypes. Our recent study suggests this founder gene was KIR2DP1 F , the functional antecedent of the now-inactive KIR2DP1 gene (Hilton et al 2017a). …”

“…Subsequently, it evolved a second lineage of alleles with T44 and C2 specificity (Hilton et al 2017a). In this way, T44 KIR2DP1 F served to replace the M44 lineage III KIR with C2-specificity that were lost from the human lineage during speciation (Abi-Rached et al 2010; Hilton et al 2017a). Provision of a single receptor with alternative allotypes that could recognize either the C1 or C2 epitopes was a major step forward.…”

“…However, although useful as an evolutionary intermediate, KIR2DP1 F was subsequently usurped by K44 KIR2DL2/3 and M44 KIR2DL1, dedicated high affinity receptors with specificity for the C1 and C2 epitopes of HLA-C, respectively. KIR2DP1 F became attenuated and subsequently inactivated due to the acquisition and propagation of a single nucleotide deletion that caused premature termination of the protein (Hilton et al 2017a; Vilches et al 2000). Inactivation of KIR2DP1 F was complete prior to the divergence of modern humans from archaic humans some 450,000 years ago (Figure 1) (Hilton et al 2017a).…”

“…KIR2DP1 F allotypes contributed a key first step in this evolution. Higher affinity K44 KIR2DP1 F allotypes accumulated in the centromeric part of CenA whereas lower affinity T44 KIR2DP1 F allotypes, many of which also had attenuated or inactivated signaling function, accumulated in CenB (Hilton et al 2017a). KIR2DL1, which is in strong linkage disequilibrium with KIR2DP1 shows a similar evolutionary trajectory.…”

Two Orangutan Species Have Evolved Different KIR Alleles and Haplotypes

“…In humans it is found in KIR2DP1 and is part of a motif (N46, T52, E71) that distinguishes it from other human lineage III KIR. Mutating human KIR2DL3 to have T52 reduced its affinity for the C1 epitope (35). Taken together these results suggest that KIR2DS15 has reduced or no binding to MHC class I.…”