Structural Basis of T Cell Receptor Recognition

T 细胞受体识别的结构基础

• 批准号: 6572862
• 负责人: IAN A WILSON
• 金额: $ 39.24万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6572862
• 关键词: CD3 molecule; CD8 molecule; MHC class I antigen; T cell receptor; T lymphocyte; X ray crystallography; antigen presentation; biological signal transduction; molecular cloning; protein purification; protein structure function; receptor binding; receptor sensitivity; tissue /cell culture

DESCRIPTION (provided by applicant): Cellular immunity is mediated largely through T-cells which interact with foreign antigens presented in the context of classical MHC class I, class II and non-classical MHC molecules. The main goal of this proposal is to understand the structural basis for T-cell recognition and T-cell signaling. The long term goal is to assemble a complete TCR signaling complex that includes the alpha/betaTCR, pMHC,CD3gamma, delta, epsilon, zeta and CD8. T-cell development will be probed through structural studies of the pre-T-cell receptor. A comparison of how gamma/delta TCRs recognize their antigens compared to alpha/betaTCRs will be evaluated from the gamma/deltaTCR/T10 or T22 nonclassical MHC complex. The alpha/beta, gamma/delta and pre-T-cell receptors all recognize and interact with CD3, but their interactions differ as the components of the various TCR types are not conserved. The CD3 components will be studied independently and as complexes with the different TCRs. In addition, the CD8 co-receptor interaction will be investigated as TCR-pMHC-CD8 complex. Many key questions will be addressed including the structural principles of TCR/MHC recognition that define MHC restriction, high affinity TCR binding is accomplished, whether conformational flexibility (entropic) is reduced in the CDR's of these high affinity TCRs, whether CD8 interacts with both pMHC and TCR, and the major question concerning the structure, stoichiometry and function of the T-cell signaling complex. This later goal is ambitious but represents the only way to probe the structural basis of T-cell signaling. The benefits from this work include an increased understanding of the immune response to microbial pathogens and elucidation of the structural basis of tolerance, autoimmunity, alloreactivity, cross-reactivity and host versus graft disease in transplantation. The IRPG represents a joint effect by two laboratories (Dr. lan Wilson, project I - structural immunology and Dr. Luc Teyton, project II - cellular immunology) to clone, express and purify sufficient quantities of alpha/betaTCR, pre-TCR, pMHC, CD8 (alpha/alpha, alpha/beta) and CD3gamma, delta, epsilon, in order to characterize biochemically and immunologically these TCR components, to crystallize each component alone and in complex with their relevant ligands and to determine their X-ray structures. The synergy between these proposals tremendously enhances and complements each individual project and substantially enhances the likely success of each.

描述（由申请人提供）：细胞免疫主要是通过与经典MHC I类，II类和非经典MHC分子相互作用的T细胞介导的。该提案的主要目标是了解T细胞识别和T细胞信号传导的结构基础。长期目标是组装一个完整的TCR信号传导复合物，其中包括Alpha/betatcr，PMHC，CD3Gamma，Delta，Epsilon，Epsilon，Zeta和CD8。 T细胞发育将通过对T前T细胞受体的结构研究进行探测。将对与α/betatcrs相比，将如何从伽马/deltatcr/t10或t22非经典MHC复合物中评估伽马/delta TCR的比较。 alpha/beta，γ/delta和前T细胞受体都识别并与CD3相互作用，但是由于各种TCR类型的组件不能保留，它们的相互作用也有所不同。 CD3组件将独立研究，并作为不同TCR的复合物进行研究。另外，CD8共受体相互作用将被研究为TCR-PMHC-CD8复合物。将解决许多关键问题，包括定义MHC限制，高亲和力TCR结合的TCR/MHC识别的结构原理，是否降低了这些高亲和力TCR的CDR的构象灵活性（熵），CD8是否与PMHC和TCR相互作用，以及与结构的主要问题相互作用，以及结构的主要问题。后来的目标是雄心勃勃的，但代表了探测T细胞信号传导结构基础的唯一方法。这项工作的好处包括对微生物病原体的免疫反应增加以及阐明耐受性，自身免疫性，同种异体性，交叉反应性以及宿主与植物疾病的结构基础。 The IRPG represents a joint effect by two laboratories (Dr. lan Wilson, project I - structural immunology and Dr. Luc Teyton, project II - cellular immunology) to clone, express and purify sufficient quantities of alpha/betaTCR, pre-TCR, pMHC, CD8 (alpha/alpha, alpha/beta) and CD3gamma, delta, epsilon, in order to characterize biochemically and从免疫学上讲，这些TCR成分，可以单独结晶每个成分，并与其相关的配体复杂并确定其X射线结构。这些建议之间的协同作用极大地增强了每个项目，并大大增强了每个项目的成功。