Resurrecting KIR2DP1: A Key Intermediate in the Evolution of Human Inhibitory NK Cell Receptors That Recognize HLA-C
Resurrecting KIR2DP1: A Key Intermediate in the Evolution of Human Inhibitory NK Cell Receptors That Recognize HLA-C
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DOI：
10.4049/jimmunol.1601835
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发表时间：
2017-03-01
影响因子：
4.4
通讯作者：
Parham, Peter
中科院分区：
文献类型：
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作者：
Hilton, Hugo G.;Blokhuis, Jeroen H.;Parham, Peter
KIR2DP1 是人类 III 系 KIR 家族的非活性成员，该家族包括所有 HLA-C 特异性受体基因。 KIR2DP1 的致命且唯一的缺陷是密码子 88 中的核苷酸缺失。在现代人类中已得到修复，这种缺失也存在于古代人类基因组中。 KIR2DP1 是多态性的，在特异性决定位置 44 处具有二态性。通过修复缺失，我们复活了 KIR2DP1(F)（KIR2DP1 的功能前身）的 11 个等位基因。我们演示了带有赖氨酸 44 的 K44-KIR2DP1(F) 如何识别 C1(+) HLA-C，而 T44-KIR2DP1(F) 如何识别 C2(+)HLA-C。其他 12 个 KIR2DP1(F) 残基的二态性可调节受体亲和力或信号传导。 KIR2DP1 和 KIR2DL1 是着丝粒 KIR 区域的邻居，并且处于紧密连锁不平衡状态。与 KIR2DL1 一样，KIR2DP1 导致了 CenA 和 CenB KIR 单倍型差异。 CenA 上编码的 C1 特异性 K44-KIR2DP1(F) 是比 CenB 上编码的减毒 C2 特异性 T44-KIR2DP1(F) 更强的受体。人类和黑猩猩的最后一个共同祖先拥有不同的 III KIR 谱系，该谱系遗传给黑猩猩，但没有遗传给人类。早期人类继承了激活性 KIR2DS4 和抑制性谱系 III KIR，可能编码 C1 特异性受体。后者催生了现代 HLA-C 受体家族。 KIR2DP1(F)具有与作为创始基因的KIR2DP1(F)一致的特性。第一个 KIR2DP1(F) 等位基因编码 K44-C1 受体；随后编码 T44-C2 受体的 KIR2DP1(F) 等位基因进化。分别编码 C1 和 C2 受体的专用 KIR2DL2/3 和 KIR2DL1 基因的出现可能导致 KIR2DP1(F) 的废弃。或者，病原体的颠覆导致了它的灭亡。 KIR2DP1(F)功能多态性的保留是通过微基因转换固定KIR2DP1(F)缺失的副作用。
KIR2DP1 is an inactive member of the human lineage III KIR family, which includes all HLA-C-specific receptor genes. 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 11 alleles of KIR2DP1(F), the functional antecedent of KIR2DP1. We demonstrate how K44-KIR2DP1(F) with lysine 44 recognized C1(+) HLA-C, whereas T44-KIR2DP1(F) recognized C2(+)HLA-C. Dimorphisms at 12 other KIR2DP1(F) residues modulate receptor avidity or signaling. KIR2DP1 and KIR2DL1 are neighbors in the centromeric KIR region and are in tight linkage disequilibrium. Like KIR2DL1, KIR2DP1 contributed to CenA and CenB KIR haplotype differences. Encoded on CenA, C1-specific K44-KIR2DP1(F) were stronger receptors than the attenuated C2-specific T44-KIR2DP1(F) 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. KIR2DP1(F) has properties consistent with KIR2DP1(F) having been the founder gene. The first KIR2DP1(F) alleles encoded K44-C1 receptors; subsequently KIR2DP1(F) alleles encoding T44-C2 receptors evolved. The emergence of dedicated KIR2DL2/3 and KIR2DL1 genes encoding C1 and C2 receptors, respectively, could have led to obsolescence of KIR2DP1(F). Alternatively, pathogen subversion caused its demise. Preservation of KIR2DP1(F) functional polymorphism was a side effect of fixation of the deletion in KIR2DP1(F) by micro gene conversion.