Immune Receptors on Cytotoxic Lymphocytes and Target Cells

颗粒介导的CTL靶细胞裂解的显著敏感性和特异性已得到充分证实。是 被认为是CTL高度选择性和快速破坏病毒感染细胞所必需的。机制 CTL介导的靶细胞破坏的潜在敏感性和功效尚不完全清楚。 最近，观察到的不同CTL克隆对靶细胞裂解的敏感性的变化提供了一个机会， 调查造成这些差异的因素，并了解更多关于靶向药物敏感性的信息。 使用含有横向移动的单体ICAM-1的支持的脂质双层控制细胞溶解， 肽-MHC（pMHC）来模拟靶细胞的表面。我们将研究免疫突触（IS） 不同靶细胞裂解敏感性CTL的颗粒形成和极化释放方式 此外，我们将利用新开发的生物传感器，基于半导体纳米晶体称为 量子点（QD），带有预定数量的紧密间隔的肽-MHC（pMHC）复合物 具有多种活性，以模拟靶细胞膜上的MHC簇集，并评估 pMHC-pMHC邻近性用于CTL活化。最后，我们提出了一个新的假设， 基于病毒学突触（VS）研究的CD 4 + CTL，其中活化的T细胞簇集gp 120-CD 4 在突触的中央簇中的相互作用。这些CD 4簇维持Lck的活化，表明 与TCR簇可能的协同作用，促进分泌结构域中溶细胞颗粒的聚集。到 我们将检验gp 120介导的信号对溶细胞颗粒模式的影响 在暴露于HIV感染细胞的平面双层模型表面的CD 4 + CTL中的极化和释放。在 同时，我们还将通过以下方法确定gp 120-CD 4相互作用对靶细胞裂解敏感性的影响： CD4+ CTL。拟议的实验有望揭示艾滋病毒的敏感破坏机制 通过CTL感染细胞，有望更好地了解CD 4 + CTL在HIV特异性免疫中的作用。 CTL杀伤病毒感染细胞机制的进一步认识 将有助于发展新的战略，以提高细胞毒性的性能， 淋巴细胞，使患者能够更好地对抗艾滋病毒感染。

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.