RECEPTORS, CO-RECEPTORS, AND COUNTER-RECEPTORS IN T CELL ACTIVATION

T 细胞激活中的受体、共受体和反受体

• 批准号: 3746482
• 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/3746482
• 关键词: B lymphocyte; T cell receptor; T lymphocyte; antigen presenting cell; cell adhesion; cell cell interaction; cell population study; cytokine; gene expression; immunoregulation; inflammation; integrins; laboratory mouse; leukocyte activation /transformation; leukopoiesis; ligands; lymphocyte proliferation; receptor binding; surface antigens; vitronectin

The interaction of the T cell receptor (TCR) with its specific ligand, peptide-MHC, is only one com-ponent 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. We have concentrated our efforts in a number of distinct areas: 1) We have shown that the interaction of the B7 family of antigens on antigen presenting cells (APC) with their co-receptors on T cells is critical for the activation of T cells and that this interaction can be mediated by expression of the B7 antigen on an APC separate from the APC presenting the nominal antigen ("trans costimulation"). The B7 family also was shown to play a critical role in the induction of CD40L, the counter-receptor for the B cell antigen CD40. The interaction of the CD40L with CD40 plays a critical role in T-B collaboration. 2) We have defined a new pathway of non-specific activation of T cells which is mediated by the Vitronectin Receptor (VNR), a member of the integrin superfamily. Ligation of the VNR on certain activated T cells could induce cytokine production by T cells that required expression of the zeta-chain, one of the components of the CD3 complex, but did not require occupancy of the TCR by its cognate antigen. The antigen-independent, TCR-dependent, VNR-mediated pathway may play an important role in chronic inflammation. The rapid induction of tyrosine phosphorylation of a 115 kD protein was shown to be one of the major effects of engagement of the VNR. 3) Continued studies of the role of the integrins in thymocyte development demonstrated that human CD4+CD8+ thymocytes could be divided into two major populations based on their differential capacity to adhere to fibronectin (FN). The FN- adherent population is less mature, expresses higher levels of CD4/CD8, and low levels of the TCR and CD69. In contrast, the non-adherent cells appear to have undergone positive selection and express lower levels of CD4 and/or CD8, high levels of the TCR, and high levels of CD69. It appears that the differentiation of the adherent population to the non- adherent is one of the critical steps of human thymocyte differentiation. Lastly, we have demonstrated that all human thymocyte subpopulations express two receptors (alpha3beta1 and alpha6beta1) for the extracellular matrix proteins, laminin and merosin. Furthermore, adhesion to these proteins can be induced by activation of the thymocytes and both laminin and merosin can costimulate thymocyte proliferation in the presence of suboptimal TCR stimulation.

T细胞受体（TCR）的相互作用与其特定配体的相互作用， 肽-MHC，只是该事件所需事件的一部分 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。 我们将精力集中在许多 不同的领域：1）我们已经证明了B7家族的相互作用 抗原呈递细胞上的抗原（APC）的抗原及其共受体 T细胞对于T细胞的激活至关重要，这是 相互作用可以通过在APC上表达B7抗原的表达来介导 与呈现名义抗原的APC分开（“ Trans） coalimulation”）。B7家族也被证明起着至关重要的作用 在诱导CD40L时，B细胞抗原的反受体 CD40。 CD40L与CD40的相互作用在 T-B协作。 2）我们定义了一种非特异性的新途径 由玻染素受体介导的T细胞的激活 （VNR），整合素超家族的成员。 VNR的连接 某些活化的T细胞可以诱导T细胞的细胞因子产生 需要表达zeta链，这是 CD3复合物，但不需要TCR的同源占用 抗原。 独立于抗原，依赖TCR的VNR介导的途径 可能在慢性炎症中起重要作用。 快速诱导 115 kD蛋白的酪氨酸磷酸化被证明是一种 VNR参与的主要影响。 3）继续研究 整联蛋白在胸腺细胞发育中的作用表明人类 CD4+ CD8+胸腺细胞可以基于两个主要种群 它们遵守纤连蛋白（FN）的差异能力。 fn- 粘附人群不那么成熟，表达较高的CD4/CD8水平， 和低水平的TCR和CD69。 相反，非粘附细胞 似乎经历了阳性选择，并表达较低的水平 CD4和/或CD8，高水平的TCR和高水平的CD69。 它 看来，遵守人群与非 - 依从物是人胸腺细胞分化的关键步骤之一。 最后，我们证明了所有人类胸腺细胞亚群 表示细胞外的两个受体（alpha3beta1和alpha6beta1） 基质蛋白，层粘连蛋白和梅罗辛。 此外，对这些 蛋白质可以通过胸腺细胞的激活和两种层粘连蛋白诱导 在存在的情况下 次优的TCR刺激。