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

项目摘要/摘要 自身免疫的定义是丧失对自身抗原的耐受性，从而导致组织被 免疫细胞。自身免疫状况在全球范围内呈上升趋势，而我们对自身免疫如何 浮现仍然是有限的。胸腺是一个高度结构化的器官，对T细胞的发育和 教育。T细胞受体(TCR)上的基因重排的性质允许识别自我和 非自身抗原。阳性选择发生在胸腺皮质，胸腺细胞在以下情况下接收生存信号 由皮质胸腺上皮细胞(CTECs)针对自身抗原进行选择。负选择发生在胸腺 髓质由髓质胸腺上皮细胞(MTECs)和各种抗原提呈细胞库驱动 (APC)包括不同亚群的树突状细胞(DC)和B细胞。三分子分子的信号强度 APC和胸腺细胞之间的复合体(TCR-肽-MHC)决定细胞的命运。胸腺细胞也会做出反应 强烈的自身抗原被删除，变得无能或转向调节性T细胞(Treg)谱系。在最佳状态下 条件T细胞选择防止自身反应性T细胞克隆释放到外周，这是一个关键过程 预防自身免疫性疾病的发生。然而，自身反应性T细胞逃逸到 对自身免疫状态下的外周组织知之甚少，而对T细胞培养的研究 初级淋巴器官在人类身上是不可行的。老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。迁徙 已知驻留的APC在人类和小鼠中都能驱动克隆删除和Treg血统。CX3CR1 表达在耐受性B细胞和单核巨噬细胞(MNP)的亚群中：DC、巨噬细胞和 单核细胞。CX3CR1+APC对外周器官中的CD4+T细胞呈递抗原。肠道中的CX3CR1+APC 转录因子Foxp3诱导外周树细胞分化。CX3CR1+APC的紧密相互作用 由于外周有CD4+T细胞，我们推测是否存在类似的CX3CR1+APC群体 在胸腺中驱动T细胞的选择，并可能在胸腺Treg的发育中发挥作用。我们的初步数据 显示胸腺中有一群CX3CR1+APC，能够抗原特异性地刺激 体外培养。这项拟议工作的长期目标是了解自身反应性T细胞是如何发展和 CX3CR1+APC驱动的胸腺逃避选择机制最终推动 自身免疫性疾病的出现。我们的研究旨在探讨APC对中枢T细胞的贡献 耐受性，目标是为自身免疫性疾病的治疗寻找潜在的新靶点。

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.