EFFECTS OF ASBESTOS ON T CELL ACTIVATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 接触石棉与诱发多种衰弱和潜在致命的人类疾病有关，如肺纤维化和间皮瘤。石棉导致纤维化和/或肿瘤转化的机制尚不清楚。细胞因子包括转化生长因子和肿瘤坏死因子是石棉肺的关键介质，缺乏TNFRI和TNFRII的小鼠不容易受到石棉引起的肺纤维化的影响。这些发现表明，免疫系统在调节石棉相关疾病方面发挥了作用。Pfau等人最近的一项研究。在蒙大拿州利比的居民中发现了免疫异常。利比受到角闪石石棉的污染，这是20世纪20年代初S至1990年期间进行的蛭石开采和加工的结果。利比居民的血清免疫球蛋白和自身抗体水平都有所提高。综上所述，这些发现强烈表明，接触闪石石棉可以调节免疫功能。为了解决闪石石棉对免疫功能的影响，这项建议侧重于CD4+T辅助细胞的激活和分化，这是产生免疫反应的关键事件。CD4+T细胞为B细胞提供细胞因子和接触性帮助，促进免疫球蛋白分泌，并允许同型转换。特异性T细胞抗原受体(TCR)与APC上同源MHC：多肽配体的相互作用迅速启动细胞内信号转导。我们和其他人已经证明，这种初始信号导致细胞质和膜结合蛋白大规模重新分布到T-APC相互作用的部位。这些分子在空间上和时间上都被分离到界面内的不同区域，称为超分子激活复合体。这些分子的聚集和分离导致免疫突触(IS)的形成。IS是充分激活和分化效应性T细胞所必需的持续细胞内信号的位置。它也是CD8+T细胞释放细胞溶解颗粒的地方，也是CD4+T细胞分泌效应细胞因子亚群的地方。免疫突触的分子组成可以对T细胞的激活状态产生重大影响。到目前为止，还没有研究在分子水平上系统地检查闪石石棉对IS形成或T淋巴细胞激活的影响。在这项建议中，我们将研究免疫突触的形成和组成。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Asbestos exposure is linked with the induction of a variety debilitating and potentially fatal human diseases such as pulmonary fibrosis and mesothelioma. The mechanisms by which asbestos induces fibrosis and/or neoplastic transformation are unclear. Cytokines including TGF¿ and TNF¿ are critical mediators of asbestosis and mice lacking both TNFRI and TNFRII are not susceptible to asbestos induced pulmonary fibrosis. These findings suggest a role for the immune system in modulating asbestos-related diseases. A recent study from Pfau et al. identified immunological abnormalities in the residents of Libby, MT. Libby was contaminated with amphibole asbestos as a result of vermiculite mining and processing that took place between the early 1920's and 1990. Libby residents have increased serum Ig and elevated levels of auto-antibodies. Taken together, these findings strongly suggest that exposure to amphibole asbestos modulates immune function. To address the effects of amphibole asbestos on immune function this proposal focuses on the activation and differentiation of CD4+ T helper cells, a key event in the generation of an immune response. CD4+ T cells provide cytokine and contact-dependent help to B cells boosting immunoglobulin secretion and allowing for isotype switching. The interaction of a specific T cell antigen receptor (TCR) with the cognate MHC:peptide ligand on an APC rapidly initiates intracellular signaling. We and others have shown that this initial signaling leads to the large-scale redistribution of cytoplasmic and membrane-bound proteins to the site of T-APC interaction. These molecules are segregated both spatially and temporally into distinct regions within the interface called supramolecular activation complexes. The accumulation and segregation of these molecules leads to formation of the immunological synapse (IS). The IS is the location of sustained intracellular signaling necessary for full activation and differentiation to effector T cells. It is also the site of cytolytic granule release by CD8+ T cells and the location of secretion for a subset of effector cytokines by CD4+ T cells. The molecular constituents of the immunological synapse can have a significant impact on the activation state of the T cells. To date, no studies have undertaken a systematic approach to examine effects of amphibole asbestos on IS formation or T lymphocyte activation at the molecular level. In this proposal we will examine the formation and characterize the composition of the immunological synapse.