Analysis of the T Cell Repertoire

T 细胞库分析

• 批准号: 6559048
• 负责人: RICHARD J. HODES
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6559048
• 关键词: CD28 molecule; CD40 molecule; T cell receptor; T lymphocyte; autoantigens; genetic strain; genetically modified animals; immune tolerance /unresponsiveness; laboratory mouse; leukocyte activation /transformation

The role of costimulation is being studied in T cell repertoire selection. Mice that are either over-expressing or deficient in costimulatory molecules B7-1 and B7-2 or the costimulatory receptor CD28 are being analyzed for expressed T cell repertoire. Additional studies are assessing the role of CD40 and CD40L in T cell repertoire selection, and have indicated that expression of CD40L is critical to negative selection mediated by endogenous mtv gene products. Two pathways of negative selection have been identified. One pathway is CD40L-dependent and acts at a relatively early stage in intra-thymic development. The second is CD40L-independent and occurs later in intra-thymic or post-thymic development. The mechanism of CD40L dependence is being investigated. Costimulatory effects are also being analyzed in the setting of tolerance to male-specific antigens in pregnant mice. The effects of polymorphic self antigens on selection are also being studies using transgenic TCR and the introduction of self antigens through trans-species crosses of Mus musculus and Mus spretus mice. It has been found that self antigens of spretus origin can mediate negative selection of T cells expressing transgenic TCR. The identification of these self antigens and the mechanism of thymic deletion and peripheral tolerance are under study in this model system.

在T细胞曲目选择中，正在研究共刺激的作用。分析表达的T细胞库的小鼠B7-1和B7-2过度表达或不足的小鼠或B7-2或共刺激受体CD28。其他研究正在评估CD40和CD40L在T细胞库中选择中的作用，并表明CD40L的表达对于由内源性MTV基因产物介导的负选择至关重要。已经确定了两种负面选择途径。一种途径是CD40L依赖性的，在胸腔内发育中起作用相对较早。第二个是与CD40L无关的，发生在胸腔内或胸腔后发育中。正在研究CD40L依赖的机制。在孕妇小鼠中对男性特异性抗原的耐受性的情况下，也正在分析共刺激作用。 多态性自抗原对选择的影响也是使用转基因TCR进行研究，并通过肌肉和墨西哥蛋白酶小鼠的跨物种杂交引入自抗原。已经发现，Spretus起源的自抗原可以介导表达转基因TCR的T细胞的负选择。这些模型系统正在研究这些自抗原以及胸腺缺失和外周耐受性的机理。