Human Lung gamma/delta T cells, Antigens and Functions

人肺 γ/δ T 细胞、抗原和功能

• 批准号: 6608188
• 负责人: ADAM WISNEWSKI
• 金额: $ 32.46万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608188
• 关键词: T cell receptor; T lymphocyte; antigen presentation; biopsy; cell population study; clinical research; cytokine; human subject; lung; major histocompatibility complex; mucosa; protein biosynthesis; tissue /cell culture

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.

描述（由申请人提供）： 人体气道代表了一种独特的微环境， 需要免疫平衡来提供对外来物质的保护 而不影响肺的重要功能γ/δ T细胞是一种 动物气道粘膜的突出特征， 作为免疫系统的哨兵，感知上皮细胞的压力， 免疫调节功能。在人类中，对γ/δ T的了解要少得多。 细胞在气道粘膜，这一直是很难研究的实际 原因虽然有限的研究表明，肺γ/δ T细胞 水平在某些人类疾病中升高，它们在正常健康中的作用， 疾病的发病机制尚未确定。我们最近报道了 人气道γ/δ T细胞系的产生和鉴定 活组织检查，确定了几种不同的刺激，能够唤起人类 γ/δ T细胞反应，并使用表达谱分析， 鉴定可能对其体内效应子功能重要的基因。我们 初步数据还表明，T细胞受体（TCR）介导的选择， 发生在人气道γ/δ T细胞中。根据这些研究， 根据文献报道的数据，我们假设（A）γ/δ T细胞 在人体呼吸道粘膜中， 抗原或损伤，并通过它们以非MHC依赖性的方式被激活。 TCR，可能通过宿主“应激”抗原，（B）γ/δ T细胞库 人气道粘膜中的细胞被限制为TCR介导的 对局部遇到的抗原的克隆选择，和（C）γ/δ T细胞 在调节肺免疫稳态中发挥重要作用， 对微环境中的上皮细胞和α/β T细胞的影响。到 为了解决这些假设，我们建议进行体外研究， 样本，而不是使用动物模型，因为以前报道的研究 表明人类γ/δ T细胞之间存在重要差异， 细胞和其他物种的那些，特别是关于抗原和TCR。 我们建议（1）从以下细胞中产生和表征γ/δ T细胞克隆： 人类气道活检，以确定气道的关键机制， γ/δ T细胞生长，包括抗原刺激， 抗原加工和MHC限制，（2）鉴定优势g/d T细胞 人气道粘膜中的细胞群，以及（3）确定气道 γ/δ T细胞对气道上皮和α/β T细胞群的影响。 这些实验的结果应该提供重要的见解， 气道粘膜γ/δ T细胞在维持人肺功能中的作用 免疫稳态