Lineage Specific Effects of IL10 In Autoimmunity

描述（由申请人提供）：IL10是一种主要的抗炎细胞因子，对设定免疫反应幅度至关重要。IL10或IL10R表达或功能的遗传变异与自身免疫性和炎症性疾病的易感性有关。许多免疫调节疗法的疗效依赖于IL10。然而，用IL10进行药物治疗在一些疾病中几乎没有益处，在一些实验环境中，用IL10进行过表达或药物治疗甚至可以促进自身免疫性炎症。我们假设il - 10在谱系特异性作用上的差异可能部分解释了其在体内活性的可变性。为了解剖IL10的谱系特异性作用，我们制造了IL10受体IL10R?的IL10选择性链条件缺陷的小鼠。在初步研究中，我们分析了IL10R？T细胞，Foxp3+调节性T细胞，B细胞和巨噬细胞在模型自身免疫性疾病，实验性过敏性脑脊髓炎（EAE）中的作用。我们的研究结果表明，IL10的促炎和抗炎功能以谱系依赖的方式分离。此外，IL10在一个谱系中具有异质作用，这些作用可能对该谱系的致病性有相反的影响。在本提案中，我们将使用EAE作为模型系统来探索IL10的谱系特异性作用如何影响自身免疫的发生和进展。我们证明，令人惊讶的是，T细胞对il - 10的反应恶化了EAE。我们假设IL10通过抑制其终端分化和促进其存活来帮助维持负责免疫病理的效应T细胞（Teff）。在Aim 1中，我们将确定il - 10对T细胞的作用如何促进EAE的免疫病理。我们将讨论IL10介导的T细胞增殖、存活和记忆的体内调节机制，免疫环境如何影响IL10的产生和作用，IL10R信号质量、动力学和大小如何影响其T特异性活性，以及IL10影响T细胞反应的相关细胞来源。与Teff相反，Foxp3+调节性T细胞的IL10反应抑制了EAE。我们假设IL10在炎症期间支持Treg寿命和抑制能力。在Aim 2中，我们将分析IL10对EAE期间Treg存活、增殖、成熟和功能的影响。IL10在全球范围内限制EAE的严重程度，但其T细胞特异性作用促进疾病。在Aim 3中，我们将确定并开始描述负责il - 10在EAE中姑息作用的细胞系。剖析IL10如何在自身免疫过程中对不同的细胞谱系产生不同的影响，将为我们提供对IL10调节作用的更好的机制理解，并有助于合理设计通过IL10途径调节炎症的新疗法。

DESCRIPTION (provided by applicant): IL10 is a predominantly anti-inflammatory cytokine that is critical in setting immune response amplitude. Genetic variation in IL10 or IL10R expression or function is associated with susceptibility to autoimmune and inflammatory diseases. The efficacy of many immunomodulatory therapies is IL10 dependent. Nevertheless, pharmacotherapy with IL10 has shown little benefit in several diseases, and in some experimental settings overexpression or pharmacologic treatment with IL10 can even promote autoimmune inflammation. We hypothesized that differences in the lineage specific effects of IL10 may in part explain the variability of its activity in vivo. To dissect IL10's lineage specifi actions, we generated mice conditionally deficient in the IL10-selective chain of the IL10 receptor, IL10R?. In preliminary studies, we analyzed deficiency of IL10R? on T cells, Foxp3+ regulatory T cells, B cells and macrophage in a model autoimmune disease, experimental allergic encephalomyelitis (EAE). Our findings indicated that pro- and anti- inflammatory functions of IL10 segregate in a lineage dependent manner. Further, IL10 has heterogeneous actions within a lineage, and these may have opposing effects on that lineage's pathogenicity. In this proposal we will use EAE as a model system to explore how the lineage specific effects of IL10 influence the development and progression of autoimmunity. We demonstrated that, surprisingly, the T cell response to IL10 worsened EAE. We hypothesize that IL10 helps sustain the effector T cells (Teff) responsible for immunopathology by inhibiting their terminal differentiation and promoting their survival. In Aim 1, we will determine how IL10's actions on T cells promote immunopathology in EAE. We will address mechanisms of IL10-mediated modulation of T cell proliferation, survival, and memory in vivo, how the immune environment influences the production and effects of IL10, how IL10R signal quality, kinetics, and magnitude influence its T-specific activities, and relevant cellular sources for IL10 affecting the T cell response. In contrast to Teff, the IL10 response of Foxp3+ regulatory T cells suppressed EAE. We hypothesize that IL10 acts to support Treg longevity and suppressive capacity during inflammation. In Aim 2 we will analyze IL10's influence on Treg survival, proliferation, maturation, and function during EAE. IL10 acts globally to limit EAE severity, yet its T cell-specific actions promote disease. In Aim 3 we will identify and begin to characterize the cell lineages responsible for IL10's palliative effects in EAE. Dissecting how IL10 variably influences different cell lineages during autoimmunity will provide us with an improved mechanistic understanding of IL10's regulatory actions, and insights that will aid in the rational design of ne therapeutics that modulate inflammation through the IL10 pathway.