HLA AND OTHER GENES AND THE TCR REPERTOIRE

这项提案的广泛目标是找出影响的例子 TCR上的单个人类白细胞抗原等位基因以及非人类白细胞抗原、非TCR基因 单阳极和双负极电池的谱系，以及 确定这些基因在多大程度上可以改变曲目 通过“正面”或“负面”的选择。这些对人类TCR的影响 曲目可能会对确定 个人对病原体和/或疾病发展的反应能力 自身免疫性疾病。我们建议对高度近亲交配的 人口。阿米什人，使用V节段特异性单抗和 定量聚合酶链式反应以及其他正在开发的方法。具体来说，我们 建议： 1)分析双阴性(DN)中的Valpha和Vbeta TCR曲目 同卵双胞胎和人类白细胞抗原完全相同和不完全相同的同胞中的细胞。这 将帮助我们确定这种T细胞是否可以表达“被禁止的” TCR可能是潜在的自身反应。 2)确定人类白细胞抗原和非人类白细胞抗原基因对Valpha TCR的影响 单个阳性(CD4+和CD8+)细胞谱系。 3)确定数量增加的关联的分子基础 表达Valpha2.3和人类白细胞抗原特异性B38的T细胞。 4)识别由人类白细胞抗原基因进行“阳性”和“阴性”选择的例子 在阿米什人中：首先，确定更多的人类白细胞抗原关联的例子 使用TCR，然后确定-TCR曲目具有的程度 被那个人类白细胞抗原等位基因的存在改变了。 5)找出亚米希人中TCR由基因决定的例子 可能代表内源性“超抗原”的非人类白细胞抗原、非TCR基因。 6)继续开发分析TCR的新方法 曲目，这将使我们能够更容易地定义 TCR谱系上个别的HLA等位基因或内源性“超抗原”。

The broad goals of this proposal are to identify examples of the influence of individual HLA alleles as well as non-HLA, non-TCR genes on the TCR repertoire of both single-positive and double-negative cells, and to determine the extent to which these genes can alter the repertoire either by "positive" or "negative" selection. Such influences on the human TCR repertoire may have profound implications in terms of determining an individual's ability to respond to pathogens and/or development of an autoimmune disease. We propose to perform these studies on a highly inbred population. the Amish, using V-segment-specific monoclonal antibodies and qPCR as well as other methods that are being developed. Specifically, we propose to: 1) analyze the Valpha and Vbeta TCR repertoire in double-negative (DN) cells in identical twins and HLA-identical and non-identical sibs. This will help us in determining whether such T cells can express "forbidden" TCR which may be potentially autoreactive. 2) determine the influence of HLA and non-HLA genes on the Valpha TCR repertoire of single positive (CD4+ and CD8+) cells. 3) determine the molecular basis for the association of increased numbers of T cells expressing Valpha2.3 and the HLA specificity B38. 4) identify examples of "positive" and "negative" selection by HLA genes in the Amish: by-first, identifying additional examples of HLA associations with TCR and then, determining-the extent to which the TCR repertoire has been altered by the presence of that HLA allele. 5) identify examples in the Amish where TCR are genetically determined by non-HLA, nonTCR genes which may represent endogenous "superantigens". 6) continue the development of new methods for analyzing the TCR repertoire which will make it possible to more easily define the effects of individual HLA alleles or endogenous "superantigens" on the TCR repertoire.