Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625 Hannover, Germany.
Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Int J Mol Sci. 2019 Mar 22;20(6):1454. doi: 10.3390/ijms20061454.
On healthy cells the non-classical HLA class Ib molecule HLA-E displays the cognate ligand for the NK cell receptor NKG2A/CD94 when bound to HLA class I signal peptide sequences. In a pathogenic situation when HLA class I is absent, HLA-E is bound to a diverse set of peptides and enables the stimulatory NKG2C/CD94 receptor to bind. The activation of CD8⁺ T cells by certain p:HLA-E complexes illustrates the dual role of this low polymorphic HLA molecule in innate and adaptive immunity. Recent studies revealed a shift in the HLA-E peptide repertoire in cells with defects in the peptide loading complex machinery. We recently showed that HLA-E presents a highly diverse set of peptides in the absence of HLA class Ia and revealed a non-protective feature against NK cell cytotoxicity mediated by these peptides. In the present study we have evaluated the molecular basis for the impaired NK cell inhibition by these peptides and determined the cell surface stability of individual p:HLA-E complexes and their binding efficiency to soluble NKG2A/CD94 or NKG2C/CD94 receptors. Additionally, we analyzed the recognition of these p:HLA-E epitopes by CD8⁺ T cells. We show that non-canonical peptides provide stable cell surface expression of HLA-E, and these p:HLA-E complexes still bind to NKG2/CD94 receptors in a peptide-restricted fashion. Furthermore, individual p:HLA-E complexes elicit activation of CD8⁺ T cells with an effector memory phenotype. These novel HLA-E epitopes provide new implications for therapies targeting cells with abnormal HLA class I expression.
在健康细胞中，非经典 HLA Ib 分子 HLA-E 与 HLA I 信号肽序列结合时，显示出 NK 细胞受体 NKG2A/CD94 的同源配体。在 HLA I 缺失的致病情况下，HLA-E 与多种肽结合，并使刺激性 NKG2C/CD94 受体结合。某些 p:HLA-E 复合物激活 CD8⁺ T 细胞表明这种低多态性 HLA 分子在先天和适应性免疫中的双重作用。最近的研究揭示了肽加载复合物机制缺陷细胞中 HLA-E 肽库的转变。我们最近表明，在没有 HLA Ia 的情况下，HLA-E 呈现出高度多样化的肽库，并揭示了这些肽介导的对 NK 细胞细胞毒性的非保护性特征。在本研究中，我们评估了这些肽对 NK 细胞抑制作用受损的分子基础，并确定了个体 p:HLA-E 复合物的细胞表面稳定性及其与可溶性 NKG2A/CD94 或 NKG2C/CD94 受体的结合效率。此外，我们分析了这些 p:HLA-E 表位被 CD8⁺ T 细胞的识别。我们表明，非典型肽提供 HLA-E 的稳定细胞表面表达，并且这些 p:HLA-E 复合物仍然以肽限制的方式结合到 NKG2/CD94 受体上。此外，个体 p:HLA-E 复合物引发具有效应记忆表型的 CD8⁺ T 细胞的激活。这些新的 HLA-E 表位为针对异常 HLA I 表达细胞的治疗提供了新的意义。
