ANTIGEN RECOGNITION BY T CELL RECEPTORS IN BASIC AND CANCER IMMUNOLOGY

基础免疫学和癌症免疫学中 T 细胞受体的抗原识别

• 批准号: 7956817
• 负责人: BRIAN BAKER
• 金额: $ 0.47万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956817
• 关键词: Antigens; Ascaridil; Autoimmune Process; Cancer Immunology Science; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Funding; Future; Grant; Immune response; Immune system; Institution; Investigation; Ligands; MART-1 Tumor Antigen; Major Histocompatibility Complex; Malignant Neoplasms; Melan-A protein; Modeling; Peptide/MHC Complex; Peptides; Property; Proteins; Research; Research Personnel; Resources; Side; Source; Synchrotrons; T-Cell Receptor; T-Lymphocyte; Time; Tumor Antigens; United States National Institutes of Health; Variant; Work; alpha-beta T-Cell Receptor; antigen binding; cancer immunotherapy; cross reactivity; design; improved; insight; interest; molecular pathology; receptor binding; research study; response; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. alpha-beta T cell receptors (TCRs) recognize peptide antigens bound and presented by major histocompatibility complex (MHC) proteins. Although T cell receptor cross-reactivity is a fundamental property of the immune system and is implicated in the immune response to cancer and numerous autoimmune pathologies, the molecular mechanisms by which TCRs can recognize and respond to diverse ligands are poorly understood. In our NIH and ACS funded work, we are seeking insight into TCR cross-reactivity through investigations of the structural and biophysical properties of TCR-pMHC interactions, and our studies involve structural determination of TCR-peptide/MHC complexes as well as unligated TCRs and peptide/MHC molecules. Structural properties are related to biophysical and immunological data. Recent findings we aim to build on with additional synchrotron time include: 1) observations that TCR recognition can proceed with cooperative structural changes occurring on both sides of the interface (Gagnon et al., J Mol Biol 363 2006 and unpublished crystallographic data) and 2) observations that subtle substitutions in antigenic peptides can have complex structural consequences, the immunological consequences of which are difficult to reconcile with current models of TCR recognition (Borbulevych et al., J Mol Biol 372 2007). The latter observations are of particular interest in the design of altered peptides for use in cancer immunotherapy (e.g., Borbulevych et al. J Immunol 174 2005). Experiments planned for the near future include structural studies of different TCRs bound to the same peptide/MHC complex and studies of peptide/MHC variants designed to elicit improved immunological responses with T cells specific for the tumor antigen Melan-A/MART-1.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 α-β T细胞受体（TCR）识别由主要组织相容性复合体（MHC）蛋白结合和呈递的肽抗原。尽管T细胞受体交叉反应性是免疫系统的基本性质，并且涉及对癌症和许多自身免疫性病理的免疫应答，但是TCR可以识别和应答不同配体的分子机制知之甚少。在我们的NIH和ACS资助的工作中，我们正在通过研究TCR-pMHC相互作用的结构和生物物理特性来深入了解TCR交叉反应性，我们的研究涉及TCR-肽/MHC复合物以及未连接的TCR和肽/MHC分子的结构测定。结构特性与生物物理学和免疫学数据有关。我们旨在利用额外的同步加速器时间建立的最近发现包括：1）观察到TCR识别可以随着界面两侧发生的合作结构变化而进行（Gagnon等人，J Mol Biol 363 2006和未发表的晶体学数据）和2）观察到抗原肽中的细微取代可具有复杂的结构后果，其免疫学后果难以与TCR识别的当前模型相协调（Borbulevych等人，J Mol Biol 372 2007）。后面的观察结果在设计用于癌症免疫治疗的改变的肽（例如，Borbulevych等人J Immunol 174 2005）。计划在不久的将来进行的实验包括对与相同肽/MHC复合物结合的不同TCR的结构研究，以及对肽/MHC变体的研究，所述肽/MHC变体被设计用于引发对肿瘤抗原Melan-A/MART-1具有特异性的T细胞的改善的免疫应答。