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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Stable masking by H-2D~d cis ligand limits Ly49A relocalization to the site of NK cell/target cell contact
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Stable masking by H-2D~d cis ligand limits Ly49A relocalization to the site of NK cell/target cell contact

机译：H-2D〜d顺式配体的稳定掩盖将Ly49A重新定位限制在NK细胞/靶细胞接触部位

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摘要

Ly49A is an inhibitory receptor, which counteracts natural killer (NK) cell activation on the engagement with H-2D~d (D~d) MHC class Ⅰ molecules (MHC-Ⅰ) on target cells. In addition to binding D~d on apposed membranes, Ly49A interacts with D~d ligand expressed in the plane of the NK cells' membrane. Indeed, multivalent, soluble MHC-Ⅰ ligand binds inefficiently to Ly49A unless the NK cells' D~d complexes are destroyed. However, it is not known whether masked Ly49A remains constitutively associated with cis D~d also during target cell interaction. Alternatively, it is possible that Ly49A has to be unmasked to significantly interact with its ligand on target cells. These two scenarios suggest distinct roles of Ly49A/D~d cis interaction for NK cell function. Here, we show that Ly49A contributes to target cell adhesion and efficiently accumulates at synapses with D~d-expressing target cells when NK cells themselves lack D~d. When NK cells express D~d, Ly49A no longer contributes to adhesion, and ligand-driven recruitment to the cellular contact site is strongly reduced. The destruction of D~d complexes on NK cells, which unmasks Ly49A, is necessary and sufficient to restore Ly49A adhesive function and recruitment to the synapse. Thus, cis D~d continuously sequesters a considerable fraction of Ly49A receptors, preventing efficient Ly49A recruitment to the synapse with D~d+ target cells. The reduced number of Ly49A receptors that can functionally interact with D~d on target cells explains the modest inhibitory capacity of Ly49A in D~d NK cells. This property renders Ly49A NK cells more sensitive to react to diseased host cells.
机译：Ly49A是一种抑制性受体，在与靶细胞上的H-2D〜d（D〜d）MHCⅠ类分子（MHC-Ⅰ）结合时抵消自然杀伤（NK）细胞的激活。除了在相对膜上结合D〜d之外，Ly49A还与NK细胞膜平面表达的D〜d配体相互作用。实际上，除非NK细胞的D-d复合物被破坏，否则多价的可溶性MHC-Ⅰ配体不能有效地与Ly49A结合。然而，尚不清楚在靶细胞相互作用期间被掩盖的Ly49A是否仍与顺式D_d组成性地缔合。或者，有可能必须将Ly49A去掩蔽以与其靶细胞上的配体显着相互作用。这两种情况表明Ly49A / D〜d顺式相互作用对NK细胞功能的独特作用。在这里，我们显示，当NK细胞自身缺乏D〜d时，Ly49A有助于靶细胞黏附并有效地与表达D〜d的靶细胞突触积累。当NK细胞表达D_d时，Ly49A不再有助于粘附，并且配体驱动的向细胞接触位点的募集被大大减少。揭露Ly49A的NK细胞上D〜d复合物的破坏是恢复Ly49A粘附功能和突触募集的必要和充分的手段。因此，顺式D_d连续隔离相当大比例的Ly49A受体，阻止了Ly49A有效地募集到具有D-d +靶细胞的突触中。能与D_d在靶细胞上发生功能性相互作用的Ly49A受体的数量减少，说明了Ly49A在D_d NK细胞中的适度抑制能力。该特性使Ly49A NK细胞对患病宿主细胞的反应更加敏感。

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