ADHESION AND SIGNALLING IN CD4 + T HELPER CELLS

CD 4 + T细胞是免疫应答的主要调节细胞。当 在适当的抗原呈递细胞（APC）刺激下，初始CD 4 + T细胞 细胞成熟为分泌细胞因子的效应细胞， 多种细胞类型的生长和分化。一些 受体-配体对在T细胞与T细胞之间的相互作用中起着关键作用， 一辆APC。CD 4辅助受体与MHC中的保守序列结合 蛋白，并与抗原特异性TCR/CD 3复合物一起，启动 胞内信号传导另外的非抗原特异性分子，如 β 1和β 2整联蛋白促进缀合物形成并增强 初始T细胞信号转导。然而，对于完全分化， 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CD 28。 T细胞-APC相互作用的复杂性和多价性使得它 很难将粘附或信号转导作用分配给任何一个 辅助或共刺激受体。因此，我们雇用了 纯化的，固定的APC蛋白，使得T细胞应答可以被 单独检查。使用这种方法，我们已经表明，成熟的CD 4 + T细胞经历TCR活化的粘附到许多辅助配体， 包括ICAM-1、纤连蛋白和玻连蛋白。令人惊讶的是，CD 4依赖 与II类蛋白的结合需要TCR和CD 4的共同参与， 相同的II类分子。因为我们之前已经证明TCR 对成熟CD 8 + T细胞的接合诱导细胞粘附至非抗原性 I类蛋白，这些发现表明辅助受体粘附MHC 蛋白质在CD 4+和CD 8 + T细胞上差异调节。 在本申请中，我们建议通过定义 控制稳定的T细胞粘附到抗原的细胞内过程 II类蛋白质。此外，我们将使用转基因小鼠， 抗原特异性α-β TCR，以及分离的 肽/II类复合物，ICAM-1，B7-1和B7-2，以更精确地定义 共刺激所必需的信号转导途径。结果 因此应该识别辅助和共刺激信号， 初始CD 4 + T细胞的活化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.