Mechanisms and consequences of CD3 rearrangement during TCR triggering

TCR 触发过程中 CD3 重排的机制和后果

• 批准号: 8664339
• 负责人: Diana Gil Pages
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-21 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664339
• 关键词: Adjuvant; Adopted; Amino Acid Sequence; Antigens; Basic Amino Acids; Beryllium; Binding; Binding Sites; Biochemical; CD3 Antigens; CD8B1 gene; Cell physiology; Chimerism; Chronic; Clonal Expansion; Communication; Comprehension; Cytoplasmic Protein; DNA Sequence Rearrangement; Data; Event; Fab Immunoglobulins; Immune; Immune response; Immunity; In Vitro; Infection; Ligands; Lipids; MHC antigen; Maps; Mature T-Lymphocyte; Mediating; Modeling; Molecular; Molecular Biology; Molecular Conformation; Molecular Target; Mono-S; Monoclonal Antibody HuM291; Morbidity - disease rate; Multiprotein Complexes; Mus; Mutate; Peptide Sequence Determination; Peptide/MHC Complex; Proline; Reagent; Regulation; SH3 Domains; Signal Transduction; Site-Directed Mutagenesis; Stretching; Structure; T cell response; T-Cell Activation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tissues; Tumor Burden; Work; adaptive immunity; arm; crosslink; design; immune function; improved; in vivo; interest; novel; protein protein interaction; public health relevance; receptor; research study; src-Family Kinases; syk Family Tyrosine Kinase; therapeutic target; tumor

DESCRIPTION (provided by applicant): There is significant interest in the development of 'T cell adjuvants', biocompounds capable of enhancing T cell immune responses against tumors or chronic infections. In order to target diseased tissue for elimination, T cells must recognize antigens via the T cell antigen receptor (TCR), and induce a conformational change in the TCR-associated CD3 complex (v). However, the mechanism(s) by which this occurs, and the precise contribution this makes to T cell immunity, are not completely understood. In this project, we propose to elucidate the protein sequences controlling CD3?c in experiments designed to inform new conceptual models regarding the structural aspects of T cell activation. We will focus on the TCR/CD3 subunits, domains, and amino acid sequences involved in CD3?c. Relevant sequences that are discovered in this manner will be mutated and expressed to ascertain their functional contribution to T cell development and activation. We will also determine the contribution that exogenous provision of CD3?c imparts to T cell function, via the use of a new reagent we have generated. This reagent can induce CD3?c without inducing other T cell signaling, and therefore it is inert to non-antigen-engaged T cells. However, the reagent appears to enhance T cell activation by weak antigens, and thus may represent a novel class of 'T cell adjuvant'. We will examine the ability of this reagent to lower the T cell activation signaling threshold, and to enhance T cell-mediated tumor rejection in mice. The information obtained from these studies will advance our comprehension of antigen recognition by T cells, and point toward CD3?c as molecular target with therapeutic potential.

描述（由申请人提供）：对“T细胞清除剂”的开发有重大兴趣，“T细胞清除剂”是能够增强针对肿瘤或慢性感染的T细胞免疫应答的生物化合物。为了靶向病变组织进行消除，T细胞必须通过T细胞抗原受体（TCR）识别抗原，并诱导TCR相关CD 3复合物的构象变化（v）。然而，这种情况发生的机制以及对T细胞免疫的确切贡献尚未完全了解。在这个项目中，我们建议阐明的蛋白质序列控制CD 3？c在实验中，旨在告知关于T细胞活化的结构方面的新概念模型。我们将集中在TCR/CD 3亚基，结构域，和氨基酸序列参与CD 3？C.以这种方式发现的相关序列将被突变和表达，以确定它们对T细胞发育和活化的功能贡献。我们还将确定外源性提供CD 3的贡献？c通过使用我们产生的新试剂赋予T细胞功能。该试剂可诱导CD 3？c而不诱导其他T细胞信号传导，因此它对非抗原接合的T细胞是惰性的。然而，该试剂似乎通过弱抗原增强T细胞活化，因此可能代表一类新的“T细胞清除剂”。我们将检查这种试剂降低T细胞活化信号传导阈值的能力，并增强小鼠中T细胞介导的肿瘤排斥反应。从这些研究中获得的信息将推进我们的理解抗原识别的T细胞，并指向CD 3？c作为具有治疗潜力的分子靶点。