T CELL RESPONSE TO MEP-REPERTOIRE AND REGULATION

有许多调节性和诱导性的影响产生和 对自身抗原如髓鞘碱性蛋白的反应的繁殖 (MBP)。抗原的形式，抗原提呈细胞的性质， 在仔细检查的T细胞谱系中的耐受水平，以及 基于抗原和T细胞受体(TCR)的调节成员 所有的电路都直接牵涉其中。这些影响的几个方面 表达的T细胞对MBP和在点上对另一个神经元的表达 蛋白质，蛋白质脂蛋白(=PLP)，将被研究。调节电路 由一个CD4+T调节细胞(抑制子诱导细胞)和一个 我们实验室已经描述了CD8+T抑制细胞，它作用于 控制与疾病有关的CD4+效应T细胞的活性。 在这项提案中，目标之一将是研究CD8+T细胞的作用 这个回路中的细胞--它的特异性和调控靶点。TCR 将采用T细胞频率较低的转基因系统 携带转基因受体。同样，监管可以通过以下方式启动 抗原，虽然它也继续与以TCR特异肽为基础的 电路，我们想要研究的是T抑制细胞 抑制MBP上的T细胞诱导决定簇。我们将调查 抗原决定簇存在的形式之间的关系 以及V基因在所选T细胞TCR中的使用情况。两种类型的 将进行耐受性实验。其中之一的焦点是 自身蛋白MBP的亚显性和隐蔽性决定因素及其 对延续神经系统疾病的重要性，实验性变态反应 脑脊髓炎。此外，多肽在诱导 将测试疾病慢性期的耐受性。我们将探索 多肽配体与MHC分子亲和力的变化如何 影响T细胞成熟方向，影响T细胞比例 Th2细胞经抗原刺激后产生Th1。这些研究 应该有助于建立更清晰的理解和潜在的治疗方法 治疗这种自身免疫性疾病。

There are many regulatory and inductive influences on the generation and propagation of response to a self-antigen such as myelin basic protein (MBP). The form of the antigen, the nature of the antigen-presenting cell, the level of tolerance in the T cell repertoire under scrutiny, and members of antigen-based and T cell receptor (TCR)-based regulatory circuits are all directly involved. Aspects of these influences on the expressed T cell repertoire to MBP and at points, to another neuronal protein, proteolipid protein (=PLP), will be studied. A regulatory circuit comprised of a CD4+ T regulatory cell (a suppressor-induced cell) and a CD8+ T suppressor cell has been described in our laboratory, which acts to control the activity of the CD4+ effector T cells responsible for disease. In this proposal, one of the aims will be to study the role of the CD8+ T cell in this circuit--its specificity and regulatory target. TCR transgenic systems will be employed with low frequencies of T cells bearing the transgenic receptor. Likewise, regulation can be initiated by antigen, and although it also proceeds to engage the TCR idiopeptide-based circuit, we would like to study the T suppressor cell induced by suppressor T cell-inducing determinants on MBP. We will investigate the relationship between the form in which the antigenic determinant exists and the V gene usage in the TCR of the selected T cells. Two types of tolerance experiments will be undertaken. One of them has as its focus the subdominant and cryptic determinants on the self protein, MBP, and their importance in perpetuating the neurologic disease, experimental allergic encephalomyelitis. Further, the effectiveness of peptides in inducing tolerance during chronic phases of disease will be tested. We will explore how a change in the affinity of peptide ligands for the MHC molecule can affect the direction of T cell maturation and influence the proportion of Th1 of Th2 cells produced after antigenic stimulation. These studies should help to establish a clearer understanding and potential therapies for this autoimmune disease.