ROLE OF CD4/CD8 MOLECULE IN T CELL SPECIFICITY

T细胞库的选择由以下表达启动： 未成熟胸腺细胞上TCR α和β链重排。 的 TCR和CD 4/CD 8辅助分子与MHC分子的相互作用 在胸腺中表达的蛋白在功能性T细胞的发育中起着关键作用。 细胞免疫。 本提案中概述的研究旨在探讨 在体外和体外， 以获得对T细胞库选择的更好理解。 在初步研究中，我们已经证明：a）Mls和I-E 某些TCR V/β链的反应性，如T细胞缺失所定义 在胸腺中表达这些V/β，不对应于抗原 体外表达相同TCR的成熟克隆的特异性; B）CD 4-CD 8 +T 携带I-E反应性V/β链的细胞通常逃避阴性选择， 在I-E小鼠品系中体内;和c）可与Mls反应的V/β 8.1+ TCR 在CD 4 + CD 8-和CD 4-CD 8-杂交瘤上，当CD 8为 在不存在CD 4的情况下表达。 这些发现表明， 进一步明确CD 4和CD 8在T细胞发育中的作用， 在胸腺和成熟T细胞的抗原特异性的库。 具体目的是：1）确定 CD 4和CD 8分子改变Mls反应性T细胞的功能特异性 2）确定为什么某些特异性的TCR β链可以被 由于它们在胸腺中的缺失而证明不显示， 阴性选择事件发生在CD 4 + CD 8+表型;和4） 确定是否所有正选择事件和负选择事件都发生在 胸腺细胞发育的CD 4 + CD 8+阶段以及这些事件是否可以 通过CD 4和CD 8独立运作。 在拟议的实验中， 旨在更好地了解细胞和分子 对T细胞的负选择和正选择两者起作用的相互作用 在胸腺中。

Selection of the T cell repertoire is initiated by the expression of rearranged TCR alpha and beta chains on immature thymocytes. The interaction of TCR and CD4/CD8 accessory molecules with the MHC molecules expressed in the thymus plays a key roll in the development of functional T cell immunity. The studies outlined in this proposal are to explore the interaction of CD4/CD8 molecules, TCR and MHC molecules both in vitro and in vivo to obtain a better understanding of T cell repertoire selection. In preliminary studies we have demonstrated that: a) the Mls and I-E reactivity of certain TCR V/Beta chains, as defined by deletion of T cells expressing these V/Beta in the thymus, does not correspond to the antigen specificity of mature clones expressing the same TCR in vitro; b) CD4-CD8+T cells bearing I-E reactive V/Beta chains often escape negative selection in vivo in I-E mouse strains; and c) the V/Beta 8.1+ TCR that can react to Mls on CD4+CD8- and CD4-CD8- hybridomas fails to react to Mls when CD8 is expressed in the absence of CD4. These findings indicate the need to further define the role of CD4 and CD8 in the development of the T cell repertoire in the thymus and in the antigen specificity of mature T cells. The specific aims are: 1) to determine how the differential expression of CD4 and CD8 molecules alters the functional specificity of Mls-reactive T cells; 2) to determine why some TCR Beta chains whose specificity can be demonstrated by virtue of their deletion in the thymus do not display and negative selection events occur at the CD4+CD8+ phenotype; and 4) to determine whether all positive and negative selection events occur at the CD4+CD8+ stage of thymocyte development and whether these events can operate through CD4 and CD8 independently. In proposed experiments are designed to provide a better understanding of the cellular and molecular interactions operating on both negative and positive selection of T cells in the thymus.