Role Of The Thymus Leukemia Antigen In Mucosal Immunity

描述(申请人提供)：肠道粘膜是许多病原体的主要入口点，也是各种炎症性疾病的靶点，包括特发性炎症性肠病(IBD)、溃疡性结肠炎和克罗恩病。新的证据表明，CD8表达的上皮内淋巴细胞(IEL)在调节肠道免疫反应中起着关键作用。最近的研究表明，CD8与胸腺白血病(TL)抗原具有高亲和力，胸腺白血病(TL)抗原是一种非经典的MHC I类分子，在肠道上皮细胞上有结构性表达。结构研究表明，TL的抗原提呈沟被阻断，表明TL与CD8之间的相互作用不依赖于TL相关的多肽。虽然TL的许多功能已经被提出，但它在肠粘膜中的免疫学作用仍然是个谜。在这个R21提案中，我们将检验TL控制IEL功能和IBD发展的假设。为了确定TL在黏膜免疫中的体内作用，我们培育了一种选择性缺失TL表达的新小鼠品系。利用这些动物，我们提出了两个综合的特异性目标来研究TL在IEL功能和IBD发展中的作用：目标1将研究TL表达对肠道T细胞功能的贡献，目标2将使用自发模型和诱导模型研究TL表达在IBD发展中的作用。该项目的长期目标是确定TL控制的粘膜免疫反应所涉及的分子机制。公共卫生研究结果：拟议研究的结果应有助于开发针对肠道感染的改进疫苗和治疗策略。此外，拟议的研究将有助于开发治疗胃肠道炎症性疾病(例如溃疡性结肠炎和克罗恩病)的新疗法。

DESCRIPTION (provided by applicant): The gut mucosa represents a major entry point for many pathogens and is the target of a variety of inflammatory conditions, including the idiopathic inflammatory bowel diseases (IBD) ulcerative colitis and Crohn's disease. Emerging evidence suggests a critical role of CD8-expressing intraepithelial lymphocytes (IEL) in regulating immune responses in the intestine. Recent studies have indicated that CD8 interacts at high affinity with the thymus leukemia (TL) antigen, a nonclassical MHC class I molecule that is constitutively expressed on intestinal epithelial cells. Structural studies have demonstrated that the putative antigen-presenting groove of TL is occluded, indicating that the interaction between TL and CD8 occurs independent of TL-associated peptides. While a number of functions for TL have been proposed, its immunological role in the gut mucosa remains enigmatic. In this R21 proposal we will test the hypothesis that TL controls IEL functions and the development of IBD. To establish the in vivo role of TL in mucosal immunity we have generated a novel mouse strain that is selectively deficient in TL expression. Using these animals, we propose two integrated specific aims to investigate the role of TL in IEL function and IBD development: Aim 1 will investigate the contribution of TL expression in intestinal T cell function and Aim 2 will investigate the role of TL expression in the development of IBD, using a spontaneous model and an induced model. The long- term goal of this project is to determine the molecular mechanisms involved in TL-controlled mucosal immune responses. PUBLIC HEALTH RELEVENCE: Results from the proposed studies should prove useful for developing improved vaccines and therapeutic strategies against intestinal infections. In addition, the proposed studies will be helpful for the development of new therapies for inflammatory conditions of the gastrointestinal tract (e.g., ulcerative colitis and Crohn's disease).