ADHESION AND SIGNALLING IN CD4 + T HELPER CELLS

CD4+T细胞是免疫反应的主要调节细胞。什么时候 在适当抗原提呈细胞(APC)的刺激下，幼稚的CD4+T细胞 细胞成熟为效应细胞，分泌细胞因子，可能调节 多种细胞类型的生长和分化。一批 受体-配体对在T细胞之间的相互作用中起着关键作用 和一台APC。CD4辅助受体与MHC中的保守序列结合 蛋白质与抗原特异的TCR/CD3复合体一起启动 细胞内信号。额外的非抗原特异性分子，如 Beta1和Beta2整合素，促进结合形成和增强 最初的T细胞信号转导。然而，为了实现完全的差异化， 目前的证据表明，幼稚T细胞还需要信号 通过共刺激受体，如CD28。 T细胞-APC相互作用的复杂、多价性质使其 很难给任何一个人分配粘附力或信号传递角色 辅助或共刺激受体。出于这个原因，我们聘请了 纯化的，固定化的APC蛋白，这样T细胞的反应可能 单独检查。使用这种方法，我们已经证明了成熟的CD4+ T细胞经历TCR激活的与许多辅助配体的黏附， 包括ICAM-1、纤维连接蛋白和玻璃体连接蛋白。令人惊讶的是，依赖于CD4的 与Il类蛋白的结合需要TCR和CD4与 同一类Il分子。因为我们之前已经证明了TCR CD8+T细胞与成熟T细胞的结合诱导细胞与非抗原性细胞的黏附 I类蛋白，这些发现表明辅助受体与MHC的黏附 蛋白质在CD4+和CD8+T细胞上有不同的调节。 在本申请中，我们建议通过定义 控制T细胞与抗原稳定黏附的细胞内过程 II类蛋白。此外，我们将使用转基因小鼠来表达 抗原特异性的α-BetaTCR与分离的 肽/II类复合体，ICAM-1，B7-1和B7-2，以更准确地定义 共刺激所必需的信号转导通路。结果是 因此应该识别辅助和共刺激信号 初始CD_4~+T细胞的激活及其向效应细胞的分化 细胞。

CD4+ T cells are major regulatory cells of the immune response. When stimulated by appropriate antigen-presenting cells (APC), naive CD4+ T cells mature into effector cells secreting cytokines that may regulate the growth and differentiation of a variety of cell types. A number of receptor-ligand pairs play key roles in the interaction between a T cell and an APC. The CD4 coreceptor binds to conserved sequences in the MHC protein, and together with the antigen-specific TCR/CD3 complex, initiates intracellular signaling. Additional nonantigen-specific molecules, such as the beta1 and beta2 integrins, facilitate conjugate formation and augment initial T cell signal transduction. For complete differentiation, however, current evidence suggests that naive T cells additionally require signals through costimulatory receptors, such as CD28. The complex, multivalent nature of the T cell-APC interaction makes it difficult to assign an adhesion or signal transducing role to any one accessory or costimulatory receptor. For this reason, we have employed purified, immobilized APC proteins, so that T cell responses may be examined in isolation. Using this approach, we have shown that mature CD4+ T cells undergo TCR-activated adhesion to many accessory ligands, including ICAM-1, fibronectin and vitronectin. Surprisingly, CD4-dependent binding to class Il proteins requires coengagement of the TCR and CD4 with the same class Il molecule. Since we had previously demonstrated that TCR engagement on mature CD8+ T cells induced cell adhesion to nonantigenic class I proteins, these findings suggest that coreceptor adhesion to MHC proteins is differentially regulated on CD4+ and CD8+ T cells. In this application, we propose to extend these studies by defining the intracellular processes that control stable T cell adhesion to antigenic class II proteins. In addition, we will employ transgenic mice expressing antigen-specific alpha-betaTCR, together with combinations of isolated peptide/class II complexes, ICAM-1, B7-1 and B7-2 to define more precisely the signal transduction pathways necessary for costimulation. The results should thus identify the accessory and costimulatory signals necessary for activation of naive CD4+ T cells, and their differentiation into effector cells.