The role of CX3CR1+ antigen presenting cells in T cell selection and central tolerance"

CX3CR1抗原呈递细胞在T细胞选择和中枢耐受中的作用"

• 批准号: 10631854
• 负责人: STEPHANIE OROZCO Figueroa
• 金额: $ 3.56万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-04-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631854
• 关键词: Affinity; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; CD4 Positive T Lymphocytes; CX3CL1 gene; Cells; Clonal Deletion; Clone Cells; Coculture Techniques; Complex; Data; Dendrites; Dendritic Cells; Development; Education; FOXP3 gene; Family; Fractalkine; Gene Rearrangement; Genetic Transcription; Goals; Human; Immune; In Situ; In Vitro; Insulin; Knowledge; Ligands; Location; Lymphocyte; Macrophage; Mediating; Molecular; Mononuclear; Mus; Nature; Organ; Outcome; Pathology; Peptide/MHC Complex; Peptides; Peripheral; Phagocytes; Population; Process; Proliferating; Reaction; Regulatory T-Lymphocyte; Reporting; Role; Shapes; Signal Transduction; Site; Structure; Structure of thymic cortex; Structure of thymic medulla; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Thymic epithelial cell; Thymocyte Development; Thymocyte Selection; Thymus Gland; Tissues; Work; anergy; autoreactive T cell; autoreactivity; cell motility; cell type; central tolerance; chemokine receptor; microbiome; migration; monocyte; mouse model; neglect; prevent; primary lymphoid organ; response; spatiotemporal; thymocyte; tool; transcription factor

PROJECT SUMMARY/ ABSTRACT Autoimmunity is defined as the loss of tolerance to self-antigen resulting in the targeted destruction of tissue by immune cells. Autoimmune conditions are on the rise globally while our knowledge on how autoimmunity emerges is still limited. The thymus is a highly structured organ that is essential for T cell development and education. The nature of the gene rearrangements on the T cell receptor (TCR) allows for recognition of self and non-self-antigens. Positive selection occurs in the thymus cortex where thymocytes receive survival signals when selected against self-antigen by cortical thymic epithelial cells (cTECs). Negative selection occurs in the thymus medulla driven by medullary thymic epithelial cells (mTECs), and a diverse repertoire of antigen presenting cells (APCs) including different subsets of dendritic cells (DCs) and B cells. The signaling strength of the tri-molecular complex (TCR-peptide-MHC) between APCs and thymocytes dictates cell fate. Thymocytes who react too strongly to self-antigens are deleted, become anergic or divert to regulatory T cell (Treg) lineage. In optimal conditions T cell selection prevents the release of autoreactive T cell clones to the periphery a critical process to prevent the onset of autoimmunity. However, the mechanisms behind the escape of autoreactive T cells to the periphery in autoimmune conditions are poorly understood, and the study of T cell education in a primary lymphoid organ is not feasible in humans. Mouse models have demonstrated to be powerful tools in thymus studies, as several developmental and functional mechanisms are evolutionary conserved. Migratory and resident APCs are known to drive clonal deletion and Treg lineage in both the humans and mice. CX3CR1 is expressed in a subset of tolerogenic B cells and Mononuclear phagocytes (MNPs): DCs, macrophages and monocytes. CX3CR1+ APCs present antigen to CD4+ T cells in peripheral organs. CX3CR1+ APCs in the gut induce differentiation of peripheral Tregs via transcription factor Foxp3. The close interaction of CX3CR1+ APCs with CD4+ T cells in the periphery lead us to hypothesize whether a similar population of CX3CR1+ APCs resides in the thymus to drive selection of T cells and may play a role in thymic Treg development. Our preliminary data shows a population of CX3CR1+ APCs in the thymus capable of antigen specific stimulation of CD4+ T cells in vitro. The long-term goal of the proposed work is to understand how autoreactive T cells develop and escape selection mechanisms in the thymus driven by CX3CR1+ APCs and ultimately drive the emergence of autoimmune disease. Our studies aim to investigate the contribution of APCs to central T cell tolerance with the goal of finding potential new targets for treatment of autoimmune disease.

项目总结/摘要 自身免疫被定义为对自身抗原的耐受性丧失，导致组织的靶向破坏， 免疫细胞。自身免疫性疾病在全球范围内呈上升趋势，而我们对自身免疫性疾病 出现仍然有限。胸腺是一个高度结构化的器官，对T细胞发育至关重要， 教育T细胞受体（TCR）上的基因重排的性质允许识别自身， 非自身抗原。阳性选择发生在胸腺皮质，胸腺细胞在此接受存活信号， 通过皮质胸腺上皮细胞（cTEC）针对自身抗原选择。负选择发生在胸腺 由胸腺髓质上皮细胞（mTECs）驱动的髓质，以及多种抗原呈递细胞 在一个实施方案中，所述抗原呈递细胞（APC）包括树突细胞（DC）和B细胞的不同子集。三分子的信号强度 APC和胸腺细胞之间的TCR-肽-MHC复合物决定细胞命运。胸腺细胞也有反应 对自身抗原反应强烈的T细胞被删除，变得无反应性或转向调节性T细胞（Treg）谱系。处于最佳 条件T细胞选择阻止自身反应性T细胞克隆释放到外周，这是一个关键过程， 防止自身免疫的发生然而，自身反应性T细胞逃逸到 自身免疫性疾病中的外周血细胞还知之甚少， 初级淋巴器官在人类中不可行。小鼠模型已被证明是强大的工具 在胸腺研究中，由于一些发育和功能机制在进化上是保守的。洄游 并且已知常驻APC在人和小鼠中驱动克隆缺失和Treg谱系。CX3CR1 在致耐受性B细胞和单核细胞吞噬细胞（MNP）的亚群中表达：DC、巨噬细胞和 单核细胞CX 3CR 1 + APC将抗原呈递给外周器官中的CD 4 + T细胞。肠道中的CX 3CR 1 + APC 通过转录因子Foxp 3诱导外周血T细胞分化CX 3CR 1 + APC的密切相互作用 与外周血中的CD 4 + T细胞相关，这使我们假设是否存在类似的CX 3CR 1 + APC群体， 在胸腺中，它可以驱动T细胞的选择，并可能在胸腺Treg发育中发挥作用。我们的初步数据 显示了胸腺中能够抗原特异性刺激CD 4 + T细胞的CX 3CR 1 + APC群， 体外这项工作的长期目标是了解自身反应性T细胞是如何发育的， 胸腺中由CX 3CR 1 + APC驱动的逃避选择机制，并最终驱动免疫应答。 自身免疫性疾病的出现。我们的研究旨在探讨APC对中枢T细胞的作用， 目的是寻找治疗自身免疫性疾病的潜在新靶点。