Molecular Basis of T Cell Recognition of Metal Ions

T细胞识别金属离子的分子基础

基本信息

批准号：
9788476
负责人：
SHAODONG DAI
金额：
$ 34.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788476
关键词：
Affect Alleles Amino Acids Antigen-Presenting Cells Area Autoimmune Diseases Beryllium Binding Blood Cations Chronic berylliosis Clone Cells Complex Contact Dermatitis Crystallization Crystallography DR1 gene Data Development Disease Exposure to Failure Goals HLA-DP2 Human Hypersensitivity Immune System Diseases Implant Ions Joints Light Lung Lung diseases MHC Interaction Medical Metal Ion Binding Metals Molecular Molecular Conformation Mutation Analysis Nature Nickel Pathologic Patients Peptide Library Peptide/MHC Complex Peptides Population Process Reaction Role Site Skin Structure Surface T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte TCR Activation Testing Therapeutic Workplace base design flexibility hip replacement arthroplasty human subject knee replacement arthroplasty peripheral blood prevent public health relevance receptor binding

项目摘要

DESCRIPTION (provided by applicant): We will study the mechanisms of human T cell hypersensitivity to beryllium (Be2+) and nickel (Ni2+) metal ions at the structural level, and confirm these mechanisms in human subjects. While evidence suggests that these metal ions are presented to pathologic T cells by an MHC molecule pre-complexed with a self-peptide, little is known about how the metal ions bind MHC, how the metal/MHC complexes are recognized by T cells, and how these processes are modulated in humans. Chronic beryllium disease (CBD) is a debilitating lung disease principally caused by workplace exposure to airborne Be2+. The disease is highly associated with MHCII alleles, particularly HLA-DP2 (DP2), that have a Glu at amino acid 69 in the ß chain helix. Our collaborators found that in human lungs, the T cell response to Be2+ is dominated by those bearing Vß5.1 with various T cell receptor (TCR) a chains, all recognizing an identical DP2/peptide/ Be2+ complex. Working with the AV22 TCR, we found that the very small Be2+ cation is buried deep in a flexible P5-P7 pocket, and influences TCR binding indirectly via local changes in the DP2-peptide surface conformation. With the goal of determining whether this mechanism is generalizable to other TCR-MHC interactions, we will test whether this flexible presentation of Be2+ applies to recognition by AV22 of Be2+/DP2 with other self- peptides, and to TCRs unrelated to AV22. Ni2+ is the most common cause of contact dermatitis, affecting 10-15% of the human population, and is also involved in reactions to metal implants such as knee and hip replacements. Here, too, specific TCR Vß motifs interact with a limited array of MHCs. In the skin, we have shown that Vß17 T cells such as the Ani2.3 T cell clone recognize Ni2+ bound to an HLA-DR52c (DR52c)-self peptide complex. Our data strongly suggest that the large Ni2+ cation is surface exposed in this complex, forming a major contact area for the TCR. Ni2+ appears to be bound to the same area of MHCII that is engaged by Be2+, i.e. in the space between the bound peptide and the MHCII ß chain. We will test this idea with structural studies on various Ni2+ specific TCRs bound to MHCII/peptide/Ni2+,and confirm the presence of Ni2+ reactive TCRs found in the blood of patients with failing metal implants due to nickel sensitization. We will pursue the following aims Aim 1 To elucidate the mechanism of presentation of HLA-DP2/ Be2+ to T cells, we will determine if Be2+ will influence engagement of the Vß5.1 TCR, AV22, indirectly via conformational changes in the DP2- self peptide surface, and determine how DP2/peptide/Be2+ is recognized by a TCR that is structurally not related to AV22, the Vß3.1 bearing TCR, RP11. Aim 2 To elucidate the mechanisms of presentation of MHCII/Ni2+ to T cells, we will define and characterize Ni2+ dependent peptides for the Vß17 TCR ANi2.3, determine whether Ni2+ is bound to DR1 in the same way as to DR52c, and whether the DR1/peptide/Ni2+/ SE9 (another Vß17 TCR) interaction is similar to that of DR52c/peptide/Ni2+/ANi2.3, and analyze the Ni2+ specific T cells in the blood of patients with joint implant failure due to nickel sensitization. Understanding the role of metal ions in these interactions will shed light on the mechanisms of metal induced immune diseases, and may help in the development of compounds that can modulate such interactions.

描述（申请人提供）：我们将在结构水平上研究人类 T 细胞对铍 (Be2+) 和镍 (Ni2+) 金属离子过敏的机制，并在人类受试者中证实这些机制，而证据表明这些金属离子是。由与自肽预复合的 MHC 分子呈递给病理性 T 细胞，但人们对金属离子如何结合 MHC、如何识别金属/MHC 复合物知之甚少慢性铍病 (CBD) 是一种使人衰弱的肺部疾病，主要由工作场所接触空气中的 Be2+ 引起，该疾病与 MHCII 等位基因，特别是 HLA-DP2 (DP2) 高度相关。我们的合作者发现，在人类肺部，T 细胞的 β 链螺旋中的第 69 位氨基酸处有一个 Glu。对 Be2+ 的反应主要是那些带有各种 T 细胞受体 (TCR) a 链的 Vß5.1，它们都识别相同的 DP2/肽/Be2+ 复合物。与 AV22 TCR 一起工作，我们发现非常小的 Be2+ 阳离子被埋得很深。在灵活的 P5-P7 口袋中，并通过 DP2 肽表面构象的局部变化间接影响 TCR 结合，目的是确定该机制是否可推广到其他 TCR-MHC。相互作用，我们将测试 Be2+ 的这种灵活呈现是否适用于 AV22 对 Be2+/DP2 与其他自肽的识别，以及与 AV22 无关的 TCR。 Ni2+ 是接触性皮炎的最常见原因，影响 10-15% 的接触性皮炎。人类群体中，也参与了对金属植入物的反应，例如膝关节和髋关节置换术，特定的 TCR Vß 基序与有限的 MHC 相互作用。在皮肤上，我们强烈表明 Vß17 T 细胞（例如 Ani2.3 T 细胞克隆）可识别与 HLA-DR52c (DR52c)-自肽复合物结合的 Ni2+。我们的数据表明，大的 Ni2+ 阳离子暴露在该复合物的表面。，形成 TCR 的主要接触区域，似乎与 Be2+ 结合的 MHCII 区域相同，即在结合的肽和结合肽之间的空间中。 MHCII β 链。我们将通过对与 MHCII/肽/Ni2+ 结合的各种 Ni2+ 特异性 TCR 进行结构研究来测试这一想法，并确认由于镍敏化而在金属植入物失败的患者血液中发现 Ni2+ 反应性 TCR 的存在。追求以下目标目标 1 为了阐明 HLA-DP2/Be2+ 向 T 细胞呈递的机制，我们将确定 Be2+ 是否会影响 T 细胞的参与Vß5.1 TCR、AV22，间接通过 DP2- 自身肽表面的构象变化，确定 DP2/肽/Be2+ 如何被结构上与 AV22（带有 TCR、RP11 的 Vß3.1）无关的 TCR 识别。 2 为了阐明 MHCII/Ni2+ 向 T 细胞呈递的机制，我们将定义并表征 Ni2+ 依赖性肽Vß17 TCR ANi2.3，确定 Ni2+ 是否以与 DR52c 相同的方式与 DR1 结合，以及 DR1/肽/Ni2+/SE9（另一个 Vß17 TCR）相互作用是否与 DR52c/肽/Ni2+/ANi2 相似。 3、分析因镍致敏导致关节植入失败患者血液中Ni2+特异性T细胞。金属离子在这些相互作用中的作用将揭示金属诱导的免疫疾病的机制，并可能有助于开发能够调节这种相互作用的化合物。