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: 8438789
• 负责人: Diana Gil Pages
• 金额: $ 29.57万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438789
• 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; leukemia; novel; protein protein interaction; 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 (CD3?c). 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(申请人提供)：人们对‘T细胞佐剂’的开发非常感兴趣，这种生物化合物能够增强T细胞对肿瘤或慢性感染的免疫反应。为了针对病变组织进行清除，T细胞必须通过T细胞抗原受体(TCR)识别抗原，并诱导TCR相关的CD3复合体(CD3？C)的构象变化。然而，这种情况发生的机制(S)以及它对T细胞免疫的确切贡献还不完全清楚。在这个项目中，我们建议在实验中阐明控制CD3？C的蛋白质序列，以提供关于T细胞激活的结构方面的新的概念模型。我们将重点研究CD3？C中涉及的TCR/CD3亚单位、结构域和氨基酸序列。以这种方式发现的相关序列将被突变和表达，以确定它们在T细胞发育和激活中的功能贡献。我们还将通过使用我们产生的一种新试剂来确定外源性CD3？C对T细胞功能的贡献。该试剂可以在不诱导其他T细胞信号的情况下诱导CD3？C，因此对非抗原结合的T细胞是惰性的。然而，该试剂似乎能增强弱抗原对T细胞的激活作用，因此可能代表了一种新的“T细胞佐剂”。我们将检验该试剂降低T细胞激活信号阈值的能力，以及增强T细胞介导的小鼠肿瘤排斥反应的能力。从这些研究中获得的信息将促进我们对T细胞识别抗原的理解，并指向CD3？C作为具有治疗潜力的分子靶点。