Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Int J Mol Sci. 2020 Oct 28;21(21):8012. doi: 10.3390/ijms21218012.
The human leukocyte antigen (HLA)-Ib molecule, HLA-F, is known as a CD4 T-cell protein and mediator of HIV progression. While HLA-Ia molecules do not have the chance to select and present viral peptides for immune recognition due to protein downregulation, HLA-F is upregulated. Post HIV infection, HLA-F loses the affinity to its activating receptor KIR3DS1 on NK cells leading to progression of the HIV infection. Several studies aimed to solve the question of the biophysical interface between HLA ligands and their cognate receptors. It became clear that even an invariant HLA molecule can be structurally modified by the variability of the bound peptide. We recently discovered the ability of HLA-F to select and present peptides and the HLA-F allele-specific peptide selection from the proteomic content using soluble HLA (sHLA) technology and a sophisticated MS method. We established recombinant K562 cells that express membrane-bound HLA-F*01:01, 01:03 or 01:04 complexes. While a recombinant soluble form of KIR3DS1 did not bind to the peptide-HLA-F complexes, acid elution of the peptides resulted in the presentation of HLA-F open conformers, and the binding of the soluble KIR3DS1 receptor increased. We used CD4/HIV and CD4/HIV cells and performed an MS proteome analysis. We could detect hemoglobin as significantly upregulated in CD4 T-cells post HIV infection. The expression of cellular hemoglobin in nonerythroid cells has been described, yet HLA-Ib presentation of hemoglobin-derived peptides is novel. Peptide sequence analysis from HLA-F allelic variants featured hemoglobin peptides as dominant and shared. The reciprocal experiment of binding hemoglobin peptide fractions to the HLA-F open conformers resulted in significantly diminished receptor recognition. These results underpin the molecular involvement of HLA-F and its designated peptide ligand in HIV immune escape.
人类白细胞抗原（HLA）-Ib 分子 HLA-F 是一种 CD4 T 细胞蛋白，也是 HIV 进展的介质。虽然由于蛋白质下调，HLA-Ia 分子没有机会选择和呈现免疫识别的病毒肽，但 HLA-F 却被上调。在感染 HIV 后，HLA-F 失去了与 NK 细胞上激活受体 KIR3DS1 的亲和力，导致 HIV 感染的进展。有几项研究旨在解决 HLA 配体与其同源受体之间的生物物理界面问题。很明显，即使是不变的 HLA 分子也可以通过结合肽的可变性来进行结构修饰。我们最近发现了 HLA-F 选择和呈现肽的能力，以及使用可溶性 HLA（sHLA）技术和复杂的 MS 方法从蛋白质组内容中选择 HLA-F 等位基因特异性肽的能力。我们建立了表达膜结合 HLA-F*01:01、01:03 或 01:04 复合物的重组 K562 细胞。虽然重组可溶性 KIR3DS1 形式不能与肽-HLA-F 复合物结合，但酸洗脱肽导致 HLA-F 开放构象的呈现，并且可溶性 KIR3DS1 受体的结合增加。我们使用 CD4/HIV 和 CD4/HIV 细胞进行了 MS 蛋白质组分析。我们可以检测到感染 HIV 后 CD4 T 细胞中血红蛋白明显上调。非红细胞细胞中已描述了细胞血红蛋白的表达，但 HLA-Ib 呈递血红蛋白衍生肽是新颖的。从 HLA-F 等位基因变体的肽序列分析中，特征是血红蛋白肽占主导地位且共享。将血红蛋白肽级分与 HLA-F 开放构象结合的反向实验导致受体识别显著减少。这些结果为 HLA-F 及其指定的肽配体在 HIV 免疫逃逸中的分子参与提供了依据。
