RECEPTORS, CORECEPTORS, AND COUNTER RECEPTORS IN T CELL ACTIVATION

T 细胞激活中的受体、辅助受体和反受体

• 批准号: 2566721
• 负责人: E M SHEVACH
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2566721
• 关键词: CD28 molecule; CD3 molecule; CD40 molecule; T cell receptor; T lymphocyte; biological signal transduction; cell cell interaction; cell differentiation; gene expression; integrins; laboratory mouse; leukocyte activation /transformation; major histocompatibility complex; monoclonal antibody; surface antigens; thymus; tissue /cell culture

The interaction of the T cell receptor (TCR) with its specific ligand, the peptide-MHC complex, is only one of the events required for the activation of antigen-specific T cells. The primary goals of our studies are to characterize cell surface antigens (co-receptors) and their soluble or cell associated ligands (counter-receptors) which play critical roles in cell-cell interaction and in the interaction of T cells with their environment. Our studies have focused on two distinct areas: 1) Although the interaction of the B7 family of costimulatory molecules with CD28 on T cells has been shown to play a critical role in providing T cell costimulation for induction of maximal T cell activation, accumulating evidence has suggested the existence of non-B7 mediated costimulation. We have characterized this alternative pathway of costimulation and demonstrated that B cells which have been activated via the CD40 antigen on their cell surface express potent B7/CD28 independent costimulatory activity which was capable of augmenting the activation of CD4+ T cells from CD28 deficient mice. To further characterize the molecules which mediate this alternative costimulatory pathway, we have developed monoclonal antibodies (mAbs) which are capable of blocking its delivery and shown that the TSA-1/sca2 antigen, a member of the Ly-6 gene family, on the activated B cells plays a key role in the delivery of the alternative costimulatory signal. 2) Integrins represent a candidate group of cell surface receptors which may control the homing and population of the thymus by T cell precursors and the subsequent migration of developing thymocytes through the thymic architecture. We have shown that blockade of the interaction of the integrin, alpha4beta1, with its ligands fibronectin (FN) and VCAM-1 inhibits the development of the earliest thymic precursor into immature CD4+ CD8+ (DP) thymocytes. Furthermore, analyses of the expression of VCAM-1 in the thymus revealed its selective localization on cortical thymic epithelial cells, while fibronectin was localized primarily in the thymic medulla. Thus, the selective localization of VCAM-1 to the cortex and FN to the medulla may play an important role in regulating the participation of each ligand in thymocyte development. Lastly, the possible role of integrins in the process of positive selection in the thymus was suggested by the demonstration that engagement of alpha4beta1 on DP thymocytes significantly potentiated anti-CD3 mediated reversal of glucocorticoid induced thymocyte apoptosis.

T细胞受体（TCR）的相互作用与其特定配体的相互作用， 肽-MHC复合物只是该肽的事件之一 抗原特异性T细胞的激活。 我们学习的主要目标 为了表征细胞表面抗原（共受体）及其 播放的可溶性或细胞相关的配体（反受体） 在细胞 - 细胞相互作用和T细胞相互作用中的关键作用 与他们的环境。 我们的研究集中在两个不同的领域： 1）虽然B7共同刺激分子家族的相互作用 已经证明，在T细胞上使用CD28在提供方面起着至关重要的作用 T细胞共刺激以诱导最大T细胞激活， 积累的证据表明存在非B7介导的 共刺激。我们已经表征了这种替代途径 共刺激并证明已经通过 CD40抗原在其细胞表面表达有效的B7/CD28独立于 能够增强激活的共同刺激活动 CD28缺陷小鼠的CD4+ T细胞。 进一步描述 介导这种替代性共刺激途径的分子，我们有 开发的单克隆抗体（mAb）能够阻止其 传递并表明TSA-1/SCA2抗原是LY-6基因的成员 家族，激活的B细胞在交付中起关键作用 替代性共刺激信号。 2）整联蛋白代表候选人 一组细胞表面受体，可以控制归巢和 T细胞前体和随后的胸腺种群 开发胸腺细胞通过胸腺结构的迁移。 我们 已经证明了整合素的相互作用alpha4beta1的封锁， 其配体纤连蛋白（FN）和VCAM-1抑制了 最早的胸腺前体进入未成熟的CD4+ CD8+（DP）胸腺细胞。 此外，对胸腺中VCAM-1表达的分析显示 它在皮质胸腺上皮细胞上的选择性定位，而 纤连蛋白主要定位在胸腺髓质中。因此， VCAM-1的选择性定位到皮质和FN的髓质可能 在调节每种配体的参与中发挥重要作用 胸腺细胞发育。最后，整联蛋白在 胸腺中阳性选择的过程是由 证明Alpha4beta1在DP胸腺细胞上的参与 明显增强糖皮质激素的抗CD3介导的逆转 诱导胸腺细胞凋亡。