Innovative Strategy to Generate Antigen-Specific Cytotoxic Lymphocytes

产生抗原特异性细胞毒性淋巴细胞的创新策略

• 批准号: 9110913
• 负责人: Chien-Fu Hung
• 金额: $ 21.14万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110913
• 关键词: ANXA5 gene; Affinity; Antigen Targeting; Antigens; Autoantigens; Avidity; Binding; CD8B1 gene; Cancer Control; Cell membrane; Clinical Management; Communicable Diseases; Couples; Data; Disease; Event; Exhibits; Frequencies; Health; Immune; Immune Tolerance; Immune system; Kinetics; Lead; Ligands; Lymphocyte; Malignant Neoplasms; Mechanics; Membrane; Modeling; Molecular; Peptide/MHC Complex; Peripheral; Phosphatidylserines; Phospholipids; Play; Population; Pre-Clinical Model; Property; Rest; Sampling; Signal Transduction; Synapses; T-Lymphocyte; TCR Activation; Technology; Tumor Antigens; Variant; annexin A5; base; crosslink; cytotoxic; disorder control; early onset; in vivo; innovation; pathogen; response; tumor; tumor progression

 DESCRIPTION (provided by applicant): Due to their unique capacity to recognize a nearly infinite array of antigen variants with exquisite sensitivity, T cells have the potential to eradicte many types of diseases, from those caused by external pathogens to those caused by transformation from within (i.e. cancer). Although it has been shown that T cells can play a key role in the control of tumor progression, tumor-specific T cells almost universally suffer from a poor capacity to recognize tumor antigen due to intricate mechanisms of central and peripheral immune tolerance. It has been established that the avidity of T cells for their target antigen is dictated by the affinity, frequency, and valency of interactions between TCR and cognate peptide-MHC (pMHC). In fact, in order for T cells to undergo full activation and expansion in response to antigen encounter, they must exhibit a high TCR affinity for cognate peptide-MHC (pMHC) (`kinetic proofreading' model), sample the antigen persistently (`serial triggering' model), or acquire high TCR occupancy by pMHC (`valency' model). The purpose of this proposal is therefore to develop a molecular approach that, in a concerted manner, couples the early onset of TCR signaling by cognate pMHC with a surge in pMHC-TCR affinity, with repeated pMHC encounter, and with widespread TCR crosslinking. We hypothesize that-on fusion to pMHC-ANXA5 behaves as a dynamic anchor that tightly engages externalized PS on the plasma membrane of cognate T cells upon TCR signaling, fastening pMHC to this membrane. We infer that in this membrane-tethered form ANXA5 stabilizes pMHC-TCR interactions, facilitates repeated antigen encounter, and prompts extensive TCR crosslinking, thereby instigating the full activation of cognate T cells with a high degree of spatial and temporal control. In this proposal, we will rigorously investigate ANXA5 fusion as a strategy for the activation of low avidity T cells by cognate pMHC. To this end, our specific aims are: 1) To characterize the effect of the ANXA5 dynamic anchor on the activation of low avidity T cells by pMHC, and 2) To characterize the molecular mechanisms by which the ANXA5 dynamic anchor augments activation of cognate T cells by pMHC. The successful implementation of this proposal will introduce unprecedented opportunities for the activation of low avidity T cells, which may lead to the successful clinical management of cancer and intractable infectious diseases.

 描述（由申请人提供）：由于T细胞具有识别几乎无限抗原变体的独特能力，具有极高的灵敏度，因此T细胞具有根除多种类型疾病的潜力，从外部病原体引起的疾病到内部转化引起的疾病（即癌症）。尽管已经显示T细胞可以在控制肿瘤进展中发挥关键作用，但是由于中枢和外周免疫耐受的复杂机制，肿瘤特异性T细胞几乎普遍地遭受识别肿瘤抗原的能力差。已经确定T细胞对其靶抗原的亲合力由TCR和同源肽-MHC（pMHC）之间相互作用的亲和力、频率和效价决定。事实上，为了使T细胞响应于抗原遭遇而经历完全活化和扩增，它们必须表现出对同源肽-MHC（pMHC）的高TCR亲和力（“动力学校正”模型），持续地对抗原取样（“连续触发”模型），或通过pMHC获得高TCR占有率（“效价”模型）。因此，本建议的目的是开发一种分子方法，其以协调一致的方式将同源pMHC的TCR信号传导的早期发作与pMHC-TCR亲和力的激增、与重复的pMHC相遇以及与广泛的TCR交联相结合。我们假设，与pMHC-ANXA 5的融合作用是一个动态的锚，在TCR信号传导后，它与同源T细胞质膜上的外部PS紧密结合，将pMHC紧固在该膜上。我们推断，在这种膜栓系形式中，ANXA 5稳定pMHC-TCR相互作用，促进重复的抗原接触，并促进广泛的TCR交联，从而引发具有高度空间和时间控制的同源T细胞的完全激活。在这个提议中，我们将严格研究ANXA 5融合作为同源pMHC激活低亲和力T细胞的策略。为此，我们的具体目标是：1）表征ANXA 5动态锚对pMHC激活低亲合力T细胞的作用，和2）表征ANXA 5动态锚增强pMHC激活同源T细胞的分子机制。该提案的成功实施将为低亲和力T细胞的激活带来前所未有的机会，这可能导致癌症和难治性感染性疾病的成功临床管理。