Immune Receptors on Cytotoxic Lymphocytes and Target Cells

CTL介导的颗粒介导的靶细胞裂解的敏感度和特异度显著提高。它是 被认为是CTL高度选择性和快速摧毁感染病毒的细胞所必需的。机制 CTL介导的靶细胞破坏的敏感性和有效性尚不完全清楚。 最近，观察到不同CTL克隆对靶细胞裂解敏感性的差异提供了一个机会 调查导致这些差异的因素，并更多地了解目标的敏感度 细胞裂解通过含有侧向可移动的单体ICAM-1和 多肽-MHC(PMHC)来模拟靶细胞的表面。我们将检查免疫突触(IS) 不同靶细胞裂解敏感度的CTL对颗粒极化和释放的形成及模式 此外，我们将利用新开发的生物传感器，这种传感器基于半导体纳米晶体，称为 量子点(QD)，带有预定数量的紧密排列的多肽-MHC(PMHC)络合物 通过不同的活性来模拟MHC在靶细胞膜上的聚集并评估其意义 PMHC-pMHC与CTL激活的亲和力。最后，我们对HIV的功能提出了一个新的假说 基于病毒学突触(VS)的研究，其中活化的T细胞聚集gp120-CD4 突触中心簇中的相互作用。这些CD4群维持LCK的激活，这表明 可能与TCR簇协同作用，促进细胞溶解颗粒在分泌区域的聚焦。至 检验假设，我们将检验gp120介导的信号对细胞溶解颗粒模式的影响。 HIV感染细胞表面模拟平面双层的CD4+CTL的极化和释放。在……里面 同时，我们还将通过以下方式确定gp120-CD4相互作用对靶细胞裂解敏感性的影响 CD4+CTL。拟议中的实验有望揭示敏感破坏艾滋病毒的机制。 通过CTL感染细胞，并承诺更好地了解CD4+CTL在HIV特异性免疫中的作用。 对CTL清除病毒感染细胞的细胞毒作用机制的再认识 将有助于开发新的策略，以增强细胞毒素的性能 并使患者能够更好地抗击艾滋病毒感染。

Remarkable sensitivity and specificity of granule-mediated target cell lysis by CTL is well established. It is thought to be necessary for highly selective and rapid destruction of virus-infected cells by CTL. Mechanisms underlying the sensitivity and efficacy of CTL mediated destruction of target cells are not entirely clear. Recently, observed variations in the sensitivity of target cell lysis by different CTL clones offer an opportunity to investigate factors responsible for these differences and to learn more about how the sensitivity of target cell lysis is controlled using supported lipid bilayers containing laterally mobile monomeric ICAM-1 and peptide-MHC (pMHC) to model the surface of target cells. We will examine immunological synapses (IS) formation and patterns of granule polarization and release by CTL with different sensitivity of target cell lysis In addition, we will utilize newly developed biosensors, based on semiconductor nanocrystals called quantum dots (QD), bearing pre-determined numbers of closely spaced peptide-MHC (pMHC) complexes with various activities to mimic MHC clustering on target cell membranes and to evaluate the significance of the pMHC-pMHC proximity for CTL activation. Finally, we propose a new hypothesis for the function of HIVspecific CD4+ CTL based on studies of virological synapse (VS) in which activated T cells cluster gp120-CD4 interactions in a central cluster of the synapse. These CD4 clusters sustain activation of Lck suggesting a possible synergy with TCR clusters that facilitates focusing of cytolytic granules in the secretory domain. To test the hypothesis we will examine the effect of gp120-mediated signaling on pattern of cytolytic granule polarization and release in CD4+ CTL exposed to planar bilayers modeling surface of HIV-infected cells. In parallel, we will also determine the impact of gp120-CD4 interactions of the sensitivity of target cell lysis by CD4+ CTL. The proposed experiments are expected to reveal mechanisms of sensitive destruction of HIV infected cells by CTL and promise to better understand the role of CD4+ CTL in HIV-specific immunity. Further understanding of the mechanisms of cytotoxicity exercised by CTL eradicating virus-infected cells will be instrumental for the development of new strategies to enhance the performance of cytotoxic lymphocytes and to enable patients to better fight HIV infection.