Segregation of HLA-C from ICAM-1 at NK cell immune synapses is controlled by its cell surface density
Segregation of HLA-C from ICAM-1 at NK cell immune synapses is controlled by its cell surface density
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DOI：
10.4049/jimmunol.177.10.6904
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Davis, Daniel M.
中科院分区：
文献类型：
--
作者：
Almeida, Catarina R.;Davis, Daniel M.
NK 细胞活性由免疫突触 (IS) 处众多激活和抑制受体的信号整合控制。然而，NK 细胞中蛋白质分离和模式化的重要性尚不清楚。在这项研究中，我们报道了靶细胞上 HLA-C 的表达水平决定了其超分子组织和 NK 细胞 IS 处与 ICAM-1 的分离，以及其抑制 NK 细胞细胞毒性的能力。在 YTS NK 细胞突触与表达低水平 HLA-C（即 10(4)/细胞表面）的靶细胞形成时，MHC I 类蛋白的多焦点模式占主导地位，而对于较高水平的表达（10(5)/细胞表面），HLA-C 簇更常见的是同质、环形或包含多个排除。蛋白质密度与其在 IS 处的模式的这种相关性独立于 ATP 或肌动蛋白驱动的过程。重要的是，ICAM-1 和 HLA-C 仅在涉及表达高水平 MHC 蛋白的靶细胞的突触处分离。对于外周血 NK 克隆，抑制细胞毒性并导致突触处 HLA-C 与 ICAM-I 分离所需的靶细胞 HLA-C 水平存在特定阈值。因此，由其表达水平决定的 HLA-C 突触组织可以直接影响 NK 细胞抑制，例如通过调节激活和抑制受体的接近程度。这首次表明抑制性 NK 细胞 IS 的组装具有重要功能。更广泛地说，细胞间接触处的蛋白质分离可以在细胞之间传递有关蛋白质表达水平的信息。
NK cell activity is controlled by the integration of signals from numerous activating and inhibitory receptors at the immunological synapse (IS). However, the importance of segregation and patterning of proteins at the NK cell IS is unknown. In this study, we report that the level of expression of HLA-C on target cells determined its supramolecular organization and segregation from ICAM-1 at the NK cell IS, as well as its capacity to inhibit NK cell cytotoxicity. At YTS NK cell synapses formed with target cells expressing low levels of HLA-C (i.e., 10(4)/cell surface), a multifocal patterning of MHC class I protein predominated, whereas for higher levels of expression (10(5)/cell surface), clusters of HLA-C were more commonly homogeneous, ring-shaped, or containing multiple exclusions. This correlation of protein density with its patterning at the IS was independent of ATP- or actin-driven processes. Importantly, ICAM-1 and HLA-C segregated only at synapses involving target cells expressing high levels of MHC protein. For peripheral blood NK clones, there were specific thresholds in the level of target cell HLA-C needed to inhibit cytotoxicity and to cause segregation of HLA-C from ICAM-I at the synapse. Thus, the synapse organization of HLA-C, determined by its level of expression, could directly influence NK cell inhibition, e.g., by regulating the proximity of activating and inhibitory receptors. For the first time, this suggests an important function for the assembly of an inhibitory NK cell IS. More broadly, segregation of proteins at intercellular contacts could transmit information about protein expression levels between cells.