Human Lung gamma/delta T cells, Antigens and Functions

描述(由申请人提供)： 人类的呼吸道代表了一个独特的微环境，在那里微妙的 需要免疫平衡才能保护身体免受外来物质的侵袭 而不会破坏肺的重要功能。伽马/增量T细胞是一种 动物呼吸道粘膜的显著特征，据信是在那里 充当免疫系统的哨兵，感知上皮压力并执行 免疫调节功能。在人类中，对伽马/增量T的了解要少得多 呼吸道粘膜中的细胞，这一直是很难研究的实用 理由。虽然有限的研究表明肺伽马/德尔塔T细胞 在某些人类疾病中水平升高，它们在正常健康和 该病的发病机制尚不清楚。我们最近报道了 人呼吸道γ/Delta T细胞系的建立及鉴定 活组织检查，确定了几种不同的刺激能够唤起人类 体外伽马/德尔塔T细胞反应并使用表达谱分析 确定可能对其体内效应功能重要的基因。我们的 初步数据还表明，T细胞受体(TCR)介导的选择 发生在人类呼吸道伽马/德尔塔T细胞中。基于这些研究和 文献中报道的数据，我们假设(A)伽马/德尔塔T细胞 在人体呼吸道粘膜对吸入物的反应中起着至关重要的作用 抗原或损伤，并以非MHC依赖的方式激活，通过其 TCR，可能是通过宿主“应激”抗原，(B)伽马/德尔塔T的谱系 人呼吸道粘膜中的细胞被限制为TCR介导的反映 对局部遇到的抗原的克隆选择，以及(C)伽马/德尔塔T细胞 在调节肺免疫动态平衡中发挥重要作用 对上皮性T细胞和α/βT细胞微环境的影响。至 为了解决这些假设，我们建议对人类进行体外研究 样本，而不是使用动物模型，因为之前报道的研究已经 证明了人类伽马/德尔塔T之间存在重要差异 细胞和其他物种的细胞，尤其是在抗原和TCR方面。 我们建议(1)从以下细胞中产生和鉴定伽马/Delta T细胞克隆 人类呼吸道活组织检查以确定对呼吸道至关重要的机制 伽马/德尔塔T细胞生长，包括抗原刺激，要求 抗原处理和MHC限制，(2)鉴定优势g/d T细胞 以及(3)确定呼吸道的影响。 呼吸道上皮细胞和α/βT细胞群上的γ/βT细胞。 这些实验的结果应该会为研究 呼吸道粘膜γ/Delta T细胞在维持人肺功能中的作用 免疫动态平衡。

DESCRIPTION (provided by applicant): The human airway represents a unique microenvironment where a delicate immunologic balance is required to provide protection from foreign substances without disrupting the vital function of the lung. Gamma/delta T cells are a prominent feature of the airway mucosa of animals where they are believed to act as sentinels of the immune system that sense epithelial stress and perform immunoregulatory functions. In humans, much less is known about gamma/delta T cells in the airway mucosa, which has been difficult to study for practical reasons. While limited studies have shown that lung gamma/delta T cells levels are elevated in certain human diseases, their role in normal health and disease pathogenesis remains undetermined. We have recently reported the generation and characterization of gamma/delta T cell lines from human airway biopsies, identified several different stimuli capable of evoking human gamma/delta T cell responses in vitro and used expression profiling to identify genes that may be important to their in vivo effector functions. Our preliminary data also suggests that T cell receptor (TCR)-mediated selection occurs among human airway gamma/delta T cells. Based on these studies and data reported in the literature, we hypothesize that (A) gamma/delta T cells in the human airway mucosa play a vital role in the host response to inhaled antigens or injury and are activated in a non MHC-dependent manner via their TCR, possibly by host "stress" antigens, (B) the repertoire of gamma/delta T cells in the human airway mucosa is restricted as a reflection of TCR-mediated clonal selection to locally encountered antigens, and (C) gamma/delta T cells play an important role in regulating lung immune homeostasis through their effects on epithelial and alpha/beta T cells in their microenvironment. To address these hypotheses, we propose to pursue in vitro studies with human samples, rather than use animal models, since previously reported studies have demonstrated that important differences exist between human gamma/delta T cells and those of other species, especially with regard to antigens and TCRs. We propose to (1) generate and characterize gamma/delta T cell clones from human airway biopsies to determine the mechanisms crucial to airway gamma/delta T cell growth, including antigenic stimuli, requirements for antigen processing and MHC restriction, (2) identify dominant g/d T cell populations in human airway mucosa, and (3) determine the effects of airway gamma/delta T cells on airway epithelial and alpha/beta T cell populations. The results of these experiments should provide important insights into the role of airway mucosal gamma/delta T cells in maintaining human pulmonary immune homeostasis.