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: 8511662
• 负责人: DALE Sannes GREGERSON
• 金额: $ 36.1万
• 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/8511662
• 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".

描述(由申请人提供)：多项研究表明，免疫系统维持调节和效应器活动的动态平衡。由于IL-2、CD25、FoxP3或AIRE缺乏或新生儿胸腺切除导致调节性T细胞活性丧失或抑制，可能导致由T细胞介导的广泛的灾难性自身免疫，其靶标包括眼组织。许多组织特异性抗原在胸腺中异位表达，部分原因是AIRE活性，这提供了产生各种调节性T细胞对自身抗原的能力，并保护其免受自身免疫的机会。这些自然调节性T细胞(NTregs)是宿主生存所必需的。在包括转化生长因子和维甲酸在内的促进Treg分化的条件下，成熟T细胞(ITregs)在外周遇到自身和外源抗原时也会被诱导产生Treg。在许多情况下，这些Treg产生的相互作用发生在淋巴组织中，包括淋巴结。也有证据表明，一些组织由明显的“常驻”树突起填充；这些组织包括皮肤、脂肪组织和胃肠道，在这些组织中，它们的局部活动似乎有助于组织动态平衡。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Tregs，我们将这一过程称为“按需”Tregs。我们在正常视网膜的实质中发现了少量的T细胞。这些T细胞的一个亚群使用Foxp3启动子表达Tregs的转基因标记。我们认为这些Treg细胞是在局部产生的，是对维持视网膜免疫稳态的持续贡献的证据。我们进一步认为，它们是由具有调节性抗原提呈细胞活性的局部视网膜树突状细胞的存在而诱导和维持的。这些假设在以下几个方面得到了探讨。目的1研究Tregs在正常静止的视网膜中的存在是否受其表达一种视网膜抗原特异性T细胞受体的促进。 目的2验证视网膜树突状细胞的功能是保护视网膜免受EAU或其他局部炎症的影响的假设，并检测其在局部损伤或视网膜炎症前后的表型。Aim 3将测试它们的来源，并检验我们的假设，即它们是“按需”制造的。