Genetic diversity in human natural killer (NK) cell receptors is linked to resistance and susceptibility to many diseases. Here, we tested the effect of this diversity on the nanoscale organization of killer cell immunoglobulin-like receptors (KIRs). Using superresolution microscopy, we found that inhibitory KIRs encoded by different genes and alleles were organized differently at the surface of primary human NK cells. KIRs that were found at low abundance assembled into smaller clusters than those formed by KIRs that were more highly abundant, and at low abundance, there was a greater proportion of KIRs in clusters. Upon receptor triggering, a structured interface called the immune synapse assembles, which facilitates signal integration and controls NK cell responses. Here, triggering of low-abundance receptors resulted in less phosphorylation of the downstream phosphatase SHP-1 but more phosphorylation of the adaptor protein Crk than did triggering of high-abundance receptors. In cells with greater KIR abundance, SHP-1 dephosphorylated Crk, which potentiated NK cell spreading during activation. Thus, genetic variation modulates both the abundance and nanoscale organization of inhibitory KIRs. That is, as well as the number of receptors at the cell surface varying with genotype, the way in which these receptors are organized in the membrane also varies. Essentially, a change in the average surface abundance of a protein at the cell surface is a coarse descriptor entwined with changes in local nanoscale clustering. Together, our data indicate that genetic diversity in inhibitory KIRs affects membrane-proximal signaling and, unexpectedly, the formation of activating immune synapses.

中文翻译：

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遗传多样性影响自然杀伤细胞受体的纳米级膜组织和信号传导。


人类自然杀伤 (NK) 细胞受体的遗传多样性与许多疾病的抵抗力和易感性有关。在这里，我们测试了这种多样性对杀伤细胞免疫球蛋白样受体（KIR）纳米级组织的影响。使用超分辨率显微镜，我们发现由不同基因和等位基因编码的抑制性 KIR 在原代人类 NK 细胞表面的组织方式不同。与丰度较高的 KIR 形成的簇相比，低丰度的 KIR 组装成更小的簇，并且在低丰度时，簇中 KIR 的比例更大。受体触发后，称为免疫突触的结构化界面就会组装起来，促进信号整合并控制 NK 细胞反应。在这里，与高丰度受体的触发相比，低丰度受体的触发导致下游磷酸酶 SHP-1 的磷酸化较少，但接头蛋白 Crk 的磷酸化较多。在 KIR 丰度较高的细胞中，SHP-1 使 Crk 去磷酸化，从而增强了 NK 细胞在激活过程中的扩散。因此，遗传变异调节抑制性 KIR 的丰度和纳米级组织。也就是说，除了细胞表面受体的数量随基因型而变化外，这些受体在膜中的组织方式也有所不同。本质上，细胞表面蛋白质平均表面丰度的变化是一个粗略的描述符，与局部纳米级聚类的变化交织在一起。总之，我们的数据表明，抑制性 KIR 的遗传多样性影响近膜信号传导，并且出人意料地影响激活免疫突触的形成。