呼吸道组织定居记忆性T细胞（TRM）的免疫学功能研究

Tissue-resident memory T cells (TRM) have a distinct microanatomical localization within nonlymphoid tissues such as skin, lung, gut and reproductive tract, and without recirculating through the blood. In many tissues, TRM cells are reported to express surface marker CD69 with or without αE integrin (CD103). In virus infectious mouse model, TRM cells are demonstrated to provide more crucial immunological protection compared with effector memory (TEM) or central memory (TCM) T cells. However, the phenotypical and functional characteristics of TRM cells in human respiratory system are less studied. In our previous studies, we found that T cells from Mycobacterium tuberculosis (M.tb) infectious patients’ pleural effusion expressed high level of CD69 low level of CD103, and CD69+ T cells compared to CD69- T cells had stronger ability to produce effector cytokines. Furthermore, mononuclear cells from inflammatory nasal polyps highly expressed CD103, and CD103+ TRM cells exhibited stronger immunological functions than CD103- TRM cells by generating more cytokines. In current study, we intend to explore following issues: to ascertain the characteristic of CD69+ and CD103+ T cells in mononuclear cells from human nasal mucosa, airway lavage fluids, and lung parenchyma; to identify the different functions of distinct memory subsets, including TRM , TEM and TCM cells; to build inflammatory transgenic DO11.10 mouse model, and analyze the possible mechanisms of the generation, maintenance, tissue-specificity and protective functions of respiratory TRM cells. Our research may reveal the basic understandings of TRM cells resided in different anatomical tissues of respiratory system, and provide theoretical basis for prevention and therapy of diseases caused by a variety of bacterial, viral infection or allergic diseases in respiratory system.

组织定居记忆性T细胞（TRM）是定居于特定组织部位、不参与外周循环的记忆性细胞，高表达CD69和/或CD103。动物研究证实，TRM细胞在皮肤、黏膜等组织中发挥重要的保护性免疫效应。但是，关于人呼吸道黏膜、气道等局部组织中TRM细胞的免疫学功能还知之甚少。在前期研究中，我们证实人结核性胸液中抗原特异性T细胞高表达CD69而低表达CD103，且CD69+ T细胞具有更强的效应功能。同时，我们在鼻黏膜预实验中发现CD103+比CD103- T细胞产生更高水平的细胞因子。本研究拟在原有基础上，系统地研究人鼻黏膜、气道（气道灌洗液）和肺组织中TRM细胞的亚群及表型特征，明确不同记忆性T细胞的功能差异性，通过DO11.10转基因小鼠体内实验探讨TRM细胞的形成、可能的调控机制和组织定居性及防御功能。该研究将揭示呼吸道不同部位TRM细胞的免疫学特征，对呼吸系统疾病的发生和发展将有一个全新的指导性认识。

组织定居记忆性T细胞（TRM）是定居于特定组织部位、不参与外周循环的记忆性细胞，高表达CD69和/或CD103。TRM细胞在人和动物的皮肤、黏膜等组织中发挥重要的保护性免疫应答，同时也与炎症和肿瘤的发生、发展和预后密切相关。本项目着重研究了人呼吸道黏膜、气道、肺等局部组织中TRM细胞的免疫学特征和功能。我们首先在不同呼吸道组织中检测到了CD69+和/或CD103+ TRM细胞，在同类组织的正常生理状态和非正常病理状态下，CD69+和/或CD103+ TRM细胞的亚群分布有明显的差异性，且不同TRM细胞亚群在功能上有着明显的差异性，CD103+ T细胞与鼻息肉的进展密切相关；在人结核性胸水中，我们发现部分记忆性CD8+ T细胞高表达CD69和CD103，而其中抗原特异性T细胞高表达CD69而低表达CD103，CD103+CD69+CD8+和CD103-CD69+CD8+ T细胞具有明显不同的效应功能。此外，我们还讨论了CD103在非T淋巴细胞中表达，发现结核性胸水来源的NK细胞也明显高表达CD103。最后，我们在小鼠模型中证实，滴鼻免疫可以有效地诱导鼻黏膜、气管和肺组织产生有保护性的免疫反应，且产生抗原特异性的长寿命组织定居记忆性T细胞，可发挥有效的防御作用。本项研究体统而全面地论述了呼吸道不同组织部位TRM细胞表型和功能的异质性，对完善呼吸系统的免疫学基本原理极为重要，对探究呼吸道疾病的发病机制将有重大意义，也可能为疾病的治疗提供一个新的靶点。