UNIQUE ROLES OF ANTIGEN PRESENTING CELLS ON T CELL TOLERANCE AND AUTOIMMUNITY

抗原呈递细胞对 T 细胞耐受和自身免疫的独特作用

• 批准号: 9759644
• 负责人: CHYI S HSIEH
• 金额: $ 43.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759644
• 关键词: Affect; American; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bone Marrow; Bone Marrow Transplantation; CD36 gene; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cell surface; Cells; Clinical; Clone Cells; Data; Dendritic Cells; Development; Diagnostic tests; Disease; Education; Effector Cell; Environment; Equilibrium; FOXP3 gene; Generations; Goals; Grant; Homeostasis; Immune; Immunity; Immunology; Knowledge; Lead; Learning; Left; Maintenance; Malignant Neoplasms; Manuscripts; Mediating; Mus; Pathway interactions; Peripheral; Play; Prevention; Process; Publishing; Regulatory T-Lymphocyte; Rest; Role; Science; Self Tolerance; Specificity; Surface Antigens; T cell differentiation; T-Lymphocyte; T-cell receptor repertoire; Testing; Th1 Cells; Thymic epithelial cell; Thymus Gland; Tissues; antigen-specific T cells; human disease; insight; novel; novel therapeutics; response; transcription factor

7. Project Summary/Abstract The development of both tolerance and autoimmunity is dependent on the presentation of self-antigens in the thymus and periphery. Thymic tolerance requires recognition of self-antigens leading to negative selection, i.e. deletion of self-reactive T cell clones; or selection into Foxp3+ regulatory T (Treg) cells, important for maintaining immune homeostasis in the periphery. In the periphery, presentation of self-antigens results in maintenance and induction of regulatory T cells to promote tolerance, but can also facilitate autoimmunity via induction of self-reactive effector cells. These processes are driven by antigen presenting cells (APCs), of which there are several subsets. Previously, we showed that Batf3-dependent CD8α+ DCs play an important role in thymic tolerance as the major recipient of antigen transfer from medullary thymic epithelial cells (mTECs), which produce a variety of self-antigens via the effect of the transcription factor Aire. Here, we propose to continue our studies on the role of CD8α+ DCs in tolerance and autoimmunity. We will continue our ongoing studies of thymic CD8α+ DCs with the goal of understanding the mechanisms of antigen transfer (Aim 1). We will also ask whether CD8α+ DCs present a unique array of self-antigens in the periphery with the goal of identifying the origin of some of these antigens (Aim 2). Finally, we will determine whether peripheral CD8α+ DCs are involved in effector vs regulatory T cell differentiation in response to self-antigens (Aim 3). If successful, this grant will offer new insights regarding the role of CD8α+ DCs in providing antigen-specific and T cell developmental niches in the thymus and periphery that may control the balance between tolerance and autoimmunity.

7.项目总结/摘要 免疫耐受和自身免疫的发生都依赖于机体内自身抗原的呈递。 胸腺和外周。胸腺耐受需要识别自身抗原，导致阴性选择，即 自身反应性T细胞克隆的缺失;或选择进入Foxp 3+调节性T（Treg）细胞，这对于 维持外周的免疫稳态。在外周，自身抗原的呈递导致 维持和诱导调节性T细胞以促进耐受，但也可以通过 自身反应性效应细胞的诱导。这些过程由抗原呈递细胞（APC）驱动， 其中有几个子集。以前，我们发现Batf 3依赖性CD 8 α+ DCs在细胞凋亡中起重要作用。 作为胸腺髓质上皮细胞抗原转移的主要受体，在胸腺耐受中的作用 mTECs（mTECs），其通过转录因子Aire的作用产生多种自身抗原。这里我们 建议继续研究CD 8 α+ DCs在免疫耐受和自身免疫中的作用。我们将继续 目前正在进行的胸腺CD 8 α+ DC的研究，目的是了解抗原转移的机制（目的 1）。我们还将探讨CD 8 α+ DCs是否在外周呈现独特的自身抗原阵列， 确定这些抗原的来源（目的2）。最后，我们将确定外周血CD 8 α+ DC参与响应于自身抗原的效应T细胞与调节T细胞的分化（目的3）。如果 成功的话，这项资助将提供关于CD 8 α+ DCs在提供抗原特异性和 胸腺和外周中的T细胞发育小生境可能控制耐受性和免疫耐受性之间的平衡。 自身免疫