Local Generation of Regulatory T Cells to Retinal Antigen

视网膜抗原调节性 T 细胞的局部生成

• 批准号: 8412152
• 负责人: DALE Sannes GREGERSON
• 金额: $ 38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8412152
• 关键词: Address; Adipose tissue; Affect; Antigen Targeting; Antigen-Presenting Cells; Antigens; Appearance; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological Assay; Blindness; Cell physiology; Cells; Competence; Dendritic Cells; Ectopic Expression; Equilibrium; Eye; Eye diseases; Frequencies; Galactosidase; Generations; Homeostasis; IL2RA gene; Immune; Immune system; Incidence; Inflammation; Inflammatory; Injury; Interleukin-2; Intestines; Knowledge; Location; Lymphoid Tissue; Maintenance; Mature T-Lymphocyte; Mediating; Mus; Neonatal; Phenotype; Play; Population; Process; Production; Publishing; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Research; Resistance; Retina; Retinal; Role; Severities; Site; Skin; Specificity; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thymectomy; Thymus Gland; Time; Tissues; Transgenic Organisms; Tretinoin; Visual; Visual impairment; Work; autoreactive T cell; in vivo; lymph nodes; promoter; research study; response; uveoretinitis

DESCRIPTION (provided by applicant): Several lines of research demonstrate that the immune system maintains a homeostatic balance of regulatory and effector activity. Loss or inhibition of the activity of regulatory T cells, by deficiency in IL-2, CD25, FoxP3, or aire, or b neonatal thymectomy, may result in widespread catastrophic autoimmunity mediated by T cells whose targets include tissues of the eye. Many tissue-specific antigens enjoy ectopic expression in the thymus, in part due to aire activity, providing the opportunity to generate a diverse repertoire of regulatory T cells to self-antigens, and protection from autoimmunity. These natural regulatory T cells (nTregs) are required for survival of the host. Tregs are also induced in the periphery from mature T cells (iTregs) upon encounter with antigens, both self and foreign, under conditions that promote Treg differentiation, including the presence of TGF and retinoic acid. In many cases these Treg-generating interactions take place in lymphoid tissues, including lymph nodes. There is also evidence that some tissues are populated by apparently "resident" Tregs; these tissues include skin, adipose tissue, and the gastro-intestinal tract where their local activity appears to contribute to tissue homeostasis. Our preliminary studies suggest that local generation of Tregs may be found during responses to retinal antigens, a process we refer to as "on-demand" Tregs. We have found a small population of T cells in the parenchyma of the normal retina. A subset of these T cells expresses a transgenic marker for Tregs using the foxp3 promoter. We propose that these Treg cells are generated locally, and are evidence of an on-going contribution to maintenance of immune homeostasis in the retina. We further propose that they are induced and maintained by the presence of local retinal dendritic cells with regulatory antigen presenting cell activity. These hypotheses are explored in the following Aims. Aim 1 asks if the presence of Tregs in the normal, quiescent retina is promoted by their expression of a T cell receptor with specificity for a retinal antigen. Aim 2 examines the hypothesis that the function of retinal Tregs is to protect the retina from EAU or other local inflammation and examines their phenotype before and after local injury or retinal inflammation. Aim 3 will test their origin, and examine our hypothesis that they are made "on-demand". PUBLIC HEALTH RELEVANCE: Inflammatory diseases of the eye pose a serious threat of blindness or visual impairment if they affect the tissues of the visual axis. The eye, and retina, have developed strategies to maintain essential immune competence, while limiting opportunities for inflammatory damage. This proposal focuses on an important component of this balance, the regulatory T cell. The search for regulatory T cell functions, their origin, and their potential for therapeutic application, is addressed in the proposed experiments.

描述（由申请人提供）：几项研究表明，免疫系统维持调节和效应活性的稳态平衡。由于IL-2、CD 25、FoxP 3或aire的缺乏或B新生儿胸腺切除术，调节性T细胞活性的丧失或抑制可导致由T细胞介导的广泛的灾难性自身免疫，其靶点包括眼组织。许多组织特异性抗原在胸腺中异位表达，部分原因是由于aire活性，提供了产生多种调节性T细胞对自身抗原的库的机会，并保护免受自身免疫。这些天然调节性T细胞（nTcells）是宿主生存所必需的。在促进Treg分化的条件下，包括TGF和视黄酸的存在下，在与自身和外来抗原相遇时，也在外周中从成熟T细胞（iTclB）诱导TclB。在许多情况下，这些产生Treg的相互作用发生在淋巴组织中，包括淋巴结。也有证据表明，一些组织中存在明显的“常驻”TdR;这些组织包括皮肤、脂肪组织和胃肠道，其中它们的局部活性似乎有助于组织稳态。我们的初步研究表明，在对视网膜抗原的反应过程中可能会发现局部产生的TdR，这一过程我们称为“按需”TdR。我们在正常视网膜的实质中发现了一小群T细胞。这些T细胞的一个亚群使用foxp 3启动子表达TcB的转基因标记。我们认为这些Treg细胞是局部产生的，并且是对视网膜中免疫稳态维持的持续贡献的证据。我们进一步提出，它们是由具有调节抗原呈递细胞活性的局部视网膜树突状细胞诱导和维持的。这些假设将在以下目标中探讨。目的1询问是否存在的正常，静止的视网膜中的T细胞受体与视网膜抗原特异性的表达促进。 目的2：研究视网膜TGFs的功能是保护视网膜免受EAU或其他局部炎症的影响，并检测其在局部损伤或视网膜炎症前后的表型。目标3将测试它们的起源，并检验我们的假设，即它们是“按需”制作的。 公共卫生关系：眼睛的炎症性疾病如果影响视轴的组织，则会造成失明或视力损害的严重威胁。眼睛和视网膜已经开发出维持基本免疫能力的策略，同时限制炎症损伤的机会。这项建议的重点是这种平衡的一个重要组成部分，调节性T细胞。调节性T细胞功能，它们的起源，以及它们的治疗应用潜力的搜索，在拟议的实验中解决。