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）：几条研究线表明，免疫系统保持了调节和效应活动活动的稳态平衡。通过IL-2，CD25，FOXP3或AIRE或B新生胸腔切除术的缺乏，调节性T细胞活性的丧失或抑制可能导致T细胞介导的广泛灾难性自身免疫性，其靶标的靶标包括眼睛的组织。许多组织特异性抗原在胸腺中享有异位表达，部分原因是AIRE活性，为自我抗原提供了多种调节性T细胞的曲目，并免受自身免疫性的保护。这些天然的调节T细胞（NTREG）是宿主存活所必需的。在促进TREG分化的条件下（包括存在TGF和视黄酸）的条件下，在成熟T细胞（ITREGS）的周围也会诱导Treg。在许多情况下，这些Treg产生的相互作用发生在包括淋巴结在内的淋巴组织中。也有证据表明，某些组织显然是“居民”的treg。这些组织包括皮肤，脂肪组织和胃肠道，其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当地产生的Treg，这是我们称为“按需” Tregs的过程。我们发现在正常视网膜的实质中发现了少数T细胞。这些T细胞的一个子集使用FOXP3启动子表示Tregs的转基因标记。我们建议这些Treg细胞是在局部生成的，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，它们是由具有调节性抗原活性的局部视网膜树突状细胞诱导和维持的。这些假设在以下目的中进行了探讨。 AIM 1询问Treg在正常，静止的视网膜中是否存在具有特异性对视网膜抗原特异性的T细胞受体的表达来促进。 AIM 2研究了视网膜Tregs的功能是保护视网膜免受EAU或其他局部炎症的影响，并检查其在局部受伤或视网膜炎症之前和之后的表型。 AIM 3将测试其起源，并研究我们被“按需”的假设。 公共卫生相关性：如果眼睛影响视觉轴组织，眼睛的炎症性疾病会构成严重的失明或视觉障碍威胁。眼睛和视网膜已经制定了维持基本免疫能力的策略，同时限制了炎症损害的机会。该提案重点介绍了这种平衡的重要组成部分，即调节T细胞。在拟议的实验中解决了寻找调节性T细胞功能，其起源和其治疗应用的潜力。