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（由适用提供）：我们将研究结构水平上的人类T细胞超敏反应（BE2+）和镍（Ni2+）金属离子的机制，并在人类受试者中确认这些机制。尽管有证据表明，这些金属离子是通过预先用自肽复杂化的MHC分子将这些金属离子呈现给病理T细胞的，但对于金属离子如何结合MHC，T细胞如何识别金属/MHC络合物，以及这些过程如何在人类中调节这些过程。慢性腹部疾病（CBD）是一种使人衰弱的肺部疾病，主要是由于工作场所暴露于空中BE2+引起的。该疾病与MHCII等位基因高度相关，尤其是HLA-DP2（DP2），它们在β链螺旋中的氨基酸69处具有GLU。我们的合作者发现，在人类肺部，T细胞中对BE2+的响应由那些带有各种T细胞接收器（TCR）A链的轴承Vß5.1构成，所有这些链条都识别出相同的DP2/肽/ BE2+复合物。使用AV22 TCR，我们发现非常小的BE2+阳离子在柔性的P5-P7袋中建造，并通过DP2肽表面构象的局部变化间接影响TCR结合。为了确定这种机制是否可以推广到其他TCR-MHC相互作用，我们将测试BE2+的这种灵活表示是否适用于BE2+/DP2的AV22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，影响了10-15％的人口，并且还参与了对金属侵入（如膝盖和髋关节替代品）的反应。在这里，特定的TCRVß基序也与有限的MHC相互作用。在皮肤中，我们表明Vß17T细胞（例如ANI2.3 T细胞克隆）识别Ni2+结合到HLA-DR52C（DR52C） - 自助肽复合物。我们的数据强烈表明，大型Ni2+阳离子在该复合物中表面暴露，形成了TCR的主要接触区域。 Ni2+似乎绑定到由BE2+参与的MHCII的同一区域。在结合肽和MHCIIβ链之间的空间中。我们将通过结构研究对与MHCII/肽/Ni2+结合的各种Ni2+特异性TCR进行测试，并确认由于镍感官而导致的金属渗透剂的患者的血液中存在Ni2+反应性TCR。我们将追求以下目标1，以阐明向T细胞呈现HLA-DP2/BE2+的机制，我们将通过间接变化DP2-自我肽表面的会议变化，并确定与DP2/PP2/peptide av2的构建，be2+是否会影响vß5.1TCR，AV22的参与度，并确定av2+ supply av2， Vß3.1轴承TCR，RP11。 AIM 2阐明了MHCII/Ni2+向T细胞的呈现机制，我们将定义和表征Vß17TCR Ani2.3的Ni2+依赖性肽，确定Ni2+确定Ni2+与DR1绑定与DR52C以及DR1/peptide/ni2+/se9（viscr）是否相同的方式与DR1绑定。 DR52C/肽/Ni2+/Ani2.3，并分析因镍传感器引起的关节植入物衰竭患者血液中的Ni2+特异性T细胞。了解金属离子在这些相互作用中的作用将阐明金属诱导的免疫机制，并可能有助于开发可以调节这种相互作用的化合物。