Airway Function-Role of gamma/delta T Cells

气道功能 - γ/δ T 细胞的作用

• 批准号: 6826410
• 负责人: WILLI K BORN
• 金额: $ 37.9万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826410
• 关键词: T cell receptor; T lymphocyte; carbohydrate receptor; fluorimetry; gene expression profiling; genetically modified animals; glycosylation; interleukin 1; interleukin 10; interleukin 6; laboratory mouse; leukocyte activation /transformation; mannose; natural killer cells; ovalbumin; protein biosynthesis; receptor expression; receptor mediated endocytosis; respiratory epithelium; respiratory function; respiratory hypersensitivity; serial analysis of gene expression; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): The broad, long-term objective of this proposal is to define the role of gammadelta T cells in the regulation of airway reactivity. This regulation is of vital importance during diseases that are associated with airway hyperresponsiveness (AHR), but the underlying mechanisms are still poorly understood. In a murine model of allergic AHR, we have found that gammadelta T cells regulate airway responsiveness, and that one particular subset suppresses and another promotes AHR. These subsets differ by their expression of TCR-Vy, but it is not yet clear how they control airway responsiveness. Because we have found that gammadelta T cells including the AHR-suppressive subset are in contact with dendritic cells (DC) within the lung, I hypothesize that specific interactions of DC with the two already identified gammadelta T cell subsets determine the AHR-regulatory influence of the gammadelta T cells. Therefore, I plan to characterize the AHR-regulatory 75 T cell populations, to define and compare the nature of their interactions with the DC, and to assess the consequences of these interactions for AHR and airway inflammation. Specifically, I propose: 1. To delineate key features of y5 T-cell-populations known to influence airway responsiveness. We will examine details of their responses to OVA-sensitization and challenge, and test, with regard to the two AHR-regulatory gammadelta T cell subsets and at the level of gene expression, our hypothesis that TCR-Vy-defined gammadelta cell-subsets are functionally different. 2. To define the cellular interactions that form the basis for AHR-regulation by gammadelta T cells. We will test the idea that gammadelta T cells continuously monitor DC in the lung, and whether monitoring involves the formation of immunological synapses with the DC. We will test whether DC induce AHR-regulatory competence in the gammadelta T cells, and whether the 75 T cells direct functional differentiation of the DC, with the predicted consequences for AHR. In the case of Vy4 + cells, we will test whether their alveolar epithelial environmenttheir functions, and in the case of VyI + cells, whether they promote allergen-responsive aB T cells. 3. To characterize molecular mechanisms involved in AHR-regulation by gammadelta T cells. We will pinpoint already identified requirements in the negative regulation of AHR by Vy4 + gammadelta T cells, namely expression of the peptide transporter TAP-l, and TNF-a. We will examine the significance of these requirements with regard to ligand recognition and activation of the gammadelta T cells, and with regard to their interaction with DC.

描述（由申请人提供）：该提案的广泛、长期目标是确定 γδ T 细胞在气道反应性调节中的作用。这种调节对于与气道高反应性 (AHR) 相关的疾病至关重要，但其潜在机制仍知之甚少。在过敏性 AHR 的小鼠模型中，我们发现 γδ T 细胞调节气道反应性，并且一个特定的子集抑制 AHR，而另一个特定的子集则促进 AHR。这些亚群的 TCR-Vy 表达有所不同，但尚不清楚它们如何控制气道反应性。因为我们发现包括 AHR 抑制子集在内的 γδ T 细胞与肺内的树突状细胞 (DC) 接触，所以我假设 DC 与两个已识别的 γδ T 细胞亚群的特定相互作用决定了 γδ T 细胞的 AHR 调节影响。因此，我计划表征 AHR 调节性 75 T 细胞群，定义和比较它们与 DC 相互作用的性质，并评估这些相互作用对 AHR 和气道炎症的影响。具体来说，我建议： 1. 描述已知影响气道反应性的 y5 T 细胞群的关键特征。我们将检查它们对 OVA 致敏和攻击的反应细节，并在两个 AHR 调节性 gammadelta T 细胞亚群和基因表达水平上测试我们的假设，即 TCR-Vy 定义的 gammadelta 细胞亚群在功能上不同。 2. 定义构成 γδ T 细胞 AHR 调节基础的细胞相互作用。我们将测试γδT细胞持续监测肺部DC的想法，以及监测是否涉及与DC形成免疫突触。我们将测试 DC 是否诱导 γδ T 细胞的 AHR 调节能力，以及 75 个 T 细胞是否指导 DC 的功能分化，以及 AHR 的预测结果。对于Vy4 + 细胞，我们将测试它们的肺泡上皮环境是否发挥功能，对于VyI + 细胞，我们将测试它们是否促进过敏原反应性aB T 细胞。 3. 表征γδ T 细胞参与AHR 调节的分子机制。我们将查明已经确定的 Vy4 + gammadelta T 细胞对 AHR 负调节的要求，即肽转运蛋白 TAP-1 和 TNF-a 的表达。我们将研究这些要求对于 γδ T 细胞的配体识别和激活以及它们与 DC 相互作用的重要性。