CD8+ T cell trafficking to the normal lung

描述（由申请人提供）：本项目旨在研究CD8+ t淋巴细胞向正常（非炎症）小鼠肺微循环（肺泡毛细血管）和相关间质组织/气道的运输。我们的长期目标是从分子角度了解调节活化的CD8+ t细胞向肺微循环迁移、这些细胞在该部位的保留以及随后细胞从血管室进入肺间质的因素。这是基于我们新发现的证据，表明活化的CD8+ t细胞保留在正常肺环境中，因为它们组成性地从肺循环血管室（即肺泡毛细血管）进入正常/非炎症肺的间质。我们的数据进一步表明，延长的t细胞滞留和进入肺间质可能是由特异性粘附受体/配体相互作用介导的，并且可能依赖于趋化因子依赖的归巢/滞留机制。为了进一步探索活化的CD8+ t细胞在正常肺中的归巢/滞留过程，我们提出以下具体目标：描述未成熟（静止）和活化的CD8+ T淋巴细胞向正常（非炎症）肺微循环的运输，以及这些细胞进入肺泡间质；2. 分析活化的CD8+ t细胞进入肺微毛细血管床并进入正常肺间质的机制。我们将采用多种策略，包括细胞和全动物成像技术来检查正常肺内转移的CD8+ t细胞的保留和区隔化。提出的分析应该为控制t淋巴细胞与肺微循环和相关间质/气道相互作用的因素以及控制这一过程的潜在机制提供新的信息。

DESCRIPTION (provided by applicant): This project is designed to investigate the trafficking of CD8+ T-lymphocytes to the pulmonary microcirculation (alveolar capillaries) and the associated interstitial tissue/airways of the normal (noninflamed) murine lungs. Our long-term objective is to understand, in molecular terms, the factors which regulate activated CD8+ T-cell migration to the pulmonary microcirculation, the retention of those cells at the site, and the subsequent egress of the cells from the vascular compartment into the lung interstitium. It is based on our emerging evidence suggesting that activated CD8+ T-cells are retained in the normal lung environment, because they constitutively egress from the pulmonary circulation vascular compartment (i.e., alveolar capillaries) into the interstitium of the normal/non-inflamed lungs. Our data further suggests that prolonged T-cell retention and egress into the lung interstitium may be mediated by specific adhesive receptor/ligand interactions, and may be dependent on a chemokine-dependent homing/retention mechanism. To further explore this process of activated CD8+ T-cell homing/retention in the normal lungs, we propose the following Specific Aims: 1. To characterize the trafficking of naive (resting) and activated CD8+ T lymphocytes to the normal (non-inflamed) pulmonary microcirculation, and the egress of these cells into the alveolar interstitium; 2. To analyze the mechanism by which activated CD8+ T-cells home to the pulmonary micro capillary bed and egress into the interstitium of the normal lung. We will employ a variety of strategies including cell and whole animal imaging techniques to examine the retention and compartmentalization of transferred CD8+ T-cells within the normal lungs. The proposed analysis should provide new information on the factors controlling the interaction of T-lymphocytes with the pulmonary microcirculation and the associated interstitium/airways, as well as, on the underlying mechanism controlling this process.