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Abstract：
Natural killer (NK) cell functions are modulated by polymorphic killer cell immunoglobulin-like receptors (KIR). Among 13 human KIR genes, which vary by presence and copy number, KIR3DL3 is ubiquitously present in every individual across diverse populations. No ligand or function is known for KIR3DL3, but limited knowledge of expression suggests involvement in reproduction, likely during placentation. With 157 human alleles, KIR3DL3 is also highly polymorphic and we show heterozygosity exceeds that of HLA-B in many populations. The external domains of catarrhine primate KIR3DL3 evolved as a conserved lineage distinct from other KIR. Accordingly, and in contrast to other KIR, we show the focus of natural selection does not correspond exclusively to known ligand binding sites. Instead, a strong signal for diversifying selection occurs in the D1 Ig domain at a site involved in receptor aggregation, which we show is polymorphic in humans worldwide, suggesting differential ability for receptor aggregation. Meanwhile in the cytoplasmic tail, the first of two inhibitory tyrosine motifs (ITIM) is conserved, whereas independent genomic events have mutated the second ITIM of KIR3DL3 alleles in all great apes. Together, these findings suggest that KIR3DL3 binds a conserved ligand, and a function requiring both receptor aggregation and inhibitory signal attenuation. In this model KIR3DL3 resembles other NK cell inhibitory receptors having only one ITIM, which interact with bivalent downstream signaling proteins through dimerization. Due to the extensive conservation across species, selection, and other unusual properties, we consider elucidating the ligand and function of KIR3DL3 to be a pressing question.
摘要：
自然杀伤（NK）细胞功能受多态杀伤细胞免疫球蛋白样受体（KIR）调节。在13个人类KIR基因中，因存在和拷贝数而异，KIR3DL3普遍存在于不同人群的每个个体中。KIR3DL3没有已知的配体或功能，但有限的表达知识表明参与生殖，可能在胎盘形成期间。有157个人类等位基因，KIR3DL3也是高度多态的，我们在许多群体中显示杂合性超过HLA-B。卡他林灵长类动物KIR3DL3的外部结构域进化为与其他KIR不同的保守谱系。因此，与其他KIR相比，我们显示自然选择的焦点并不完全对应于已知的配体结合位点。相反，多样化选择的强烈信号发生在D1Ig结构域参与受体聚集的位点，我们展示的是全世界人类的多态，表明受体聚集的不同能力。同时在胞质尾部,两个抑制性酪氨酸基序（ITIM）中的第一个是保守的，而独立的基因组事件已经突变了所有大猿中KIR3DL3等位基因的第二个ITIM。一起,这些发现表明KIR3DL3结合保守的配体，和需要受体聚集和抑制信号衰减的功能。在此模型中，KIR3DL3类似于仅具有一个ITIM的其他NK细胞抑制性受体，通过二聚化与二价下游信号蛋白相互作用。由于跨物种的广泛保护，选择,和其他不寻常的属性，我们认为阐明KIR3DL3的配体和功能是一个紧迫的问题。
