Local Control and Regulation of Retinal Autoimmunity

项目摘要/摘要 效应性T细胞、调节性T细胞和无能T细胞的平衡和功能对维持 免疫动态平衡。缺乏调节性T细胞导致自身抗原介导的自身免疫 特定的效应器T细胞，其靶点可以包括眼睛组织。虽然大多数Tregs起源于 胸腺，我们之前的研究表明，对视网膜自身抗原的反应，Tregs可以在局部产生 在视网膜中来自传统的CD4T细胞，这一过程我们称之为“按需”Treg生成。T细胞 在无共刺激信号或存在的情况下识别抗原-MHC-II复合体 抑制信号可以诱导T细胞无能，一种功能无反应和不增殖的状态。 因此，无能T细胞的产生可能是维持视网膜免疫的另一个重要机制 动态平衡。我们观察到少量的T细胞和一群髓系细胞(小胶质细胞)， 它们的子集可以在视网膜内充当传统的树突状细胞。因此，我们假设有一个本地的， 视网膜内持续产生视网膜自身抗原特异性树突状细胞和无能T细胞 对视网膜免疫动态平衡以及T细胞、视网膜小胶质细胞和可能的非 髓系视网膜细胞决定视网膜T细胞的性质和命运。这一假说将分三部分进行探讨。 目的将R161H小鼠自发性视网膜自身免疫模型与转基因小鼠联合使用 允许追踪和耗尽树突状细胞、小胶质细胞和树突状细胞。 目的1：这一目标将确定视网膜小胶质细胞，特别是树突状细胞亚群在抗原中所起的作用 在视网膜中导致自身免疫发病机制的表现。 目标2：这个目标将定义和区分视网膜小胶质细胞与非髓系小胶质细胞的作用 视网膜细胞在视网膜内产生无能和调节性T细胞。 目标3：这个目标将是使用视网膜小胶质细胞或其他局部治疗性操作的转化性研究 抗原提呈细胞限制T细胞共刺激并促进无能和调节性T细胞的产生 以限制对视网膜的炎性损伤。

Project Summary/Abstract The balance and function of effector T cells, regulatory T cells, and anergic T cells are critical for maintaining immune homeostasis. Lack of regulatory T cells (Tregs) leads to autoimmunity mediated by self-antigen specific effector T cells whose targets can include tissues of the eye. Although most Tregs originate in the thymus, our previous studies suggest that in response to retinal self-antigens, Tregs can be generated locally in the retina from conventional CD4+ T cells, a process we refer to as "on-demand" Treg generation. T cell recognition of antigen-MHC-II complexes in the absence of costimulatory signals or in the presence of inhibitory signals can induce anergy, a state of functional unresponsiveness and non-proliferation in T cells. Thus, generation of anergic T cells may be another important mechanism for maintaining retinal immune homeostasis. We have observed a small number of T cells and a population of myeloid cells (microglia), a subset of which can act as conventional dendritic cells within the retina. Thus, we hypothesize there is a local, continual generation of retinal self-antigen specific Tregs and anergic T cells within the retina that contributes to retinal immune homeostasis and that the interaction between T cells, retinal microglia, and possibly non- myeloid retinal cells determines the nature and fate of retinal T cells. This hypothesis will be explored in three aims using the R161H mouse model of spontaneous retinal autoimmunity in conjunction with transgenic mice that allow for the tracking and depletion of dendritic cells, microglia, and Tregs. Aim 1: This aim will define the role that retinal microglia, particularly the dendritic cell subset, plays in antigen presentation that leads to autoimmune pathogenesis in the retina. Aim 2: This aim will define and distinguish the roles that resident retinal microglia versus the non-myeloid retinal cells play in production of anergic and regulatory T cells within the retina. Aim 3: This aim will be translational studies using local therapeutic manipulation of retinal microglia or other antigen presenting cells to limit T cell co-stimulation and promote generation of anergic and regulatory T cells to limit inflammatory injury to the retina.