Tissue specific control of CD4+ T cells via IL-10 signaling

通过 IL-10 信号传导对 CD4 T 细胞进行组织特异性控制

• 批准号: 310356505
• 负责人: Professor Dr. Samuel Huber
• 金额: --
• 依托单位: I. Medizinische Klinik und Poliklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/310356505?language=en
• 关键词: Tissue; specific; control; CD4+; cells

IL-10 is an important anti-inflammatory cytokine that is produced by various types of immune cells. Accordingly deficiency in IL-10 correlates with the development of chronic inflammatory diseases. Thus, IL-10 can act on antigen presenting cells and inhibit their maturation, thereby controlling CD4+ T-cell responses indirectly. Furthermore we and others have recently reported that IL-10 can also act on T cells directly thereby controlling inflammation of the intestine: IL-10 can directly act on regulatory T cells (Foxp3+Treg) promoting their suppressive function thereby indirectly controlling TH17 cells. Additionally IL-10 can also directly interact with TH17 cells thereby controlling their phenotype and expansion. On the contrary, it was shown in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)) that IL-10 is also able to directly promote survival of memory CD4+ T cells and therefore to support neuronal inflammation. In line with these seemingly contradictory data our preliminary results suggest important difference of the effect of IL-10 on different T helper cell subsets between the CNS (central nervous system) and the intestine.Based on these findings, we hypothesize that IL-10 has dual effects on CD4+ T cells, which can be both direct and indirect depending on the specific T helper cell subtype as well as tissue specific factors. In order to test this hypothesis we will use mouse models of intestinal and neural inflammation. Furthermore, we will use reporter Knock In mouse models (Foxp3 mRFP x Il-10 eGFP x Il-17a FP635) and transgenic mice with impaired (Cd4-dnIL-10R) or complete abrogation of IL-10 signaling (conditional IL-10R alpha Knockout) in order to specifically analyze the role of IL-10 signaling in Foxp3+ Treg and TH17 cells. We aim to first analyze whether the IL-10/IL-10(R)eceptor axis is differentially regulated during the cause of neuronal and intestinal inflammation. In a second step, we will determine if IL-10 signaling plays a differential role in regulating TH17 cells and Foxp3+ Treg during the induction and effector phase of EAE. Additionally, we will elucidate the tissue-specific role of IL-10 in the control of T-cell responses in the central nervous system (CNS). To this end, we will i) investigate the role of IL-10 for the Foxp3+ Treg-mediated control of TH17 cells in the CNS, ii) test whether Foxp3+ Treg control their activity in the CNS via a positive feedback loop of IL-10 signaling and iii) identify candidate genes that are regulated by IL-10 specifically in Foxp3+Treg in the CNS. These investigations will lead to a better understanding of the regulation of inflammation by IL-10 and may build the basis for new tissue-specific therapies for the treatment of autoimmune and chronic inflammatory diseases of the CNS and intestine.

IL-10是一种重要的抗炎细胞因子，由各种类型的免疫细胞产生。因此，IL-10的缺乏与慢性炎性疾病的发展相关。因此，IL-10可以作用于抗原呈递细胞并抑制其成熟，从而间接控制CD 4 + T细胞应答。此外，我们和其他人最近报道IL-10也可以直接作用于T细胞，从而控制肠道炎症：IL-10可以直接作用于调节性T细胞（Foxp 3 +Treg），促进其抑制功能，从而间接控制TH 17细胞。此外，IL-10还可以直接与TH 17细胞相互作用，从而控制它们的表型和扩增。相反，在多发性硬化症（实验性自身免疫性脑脊髓炎（EAE））的小鼠模型中显示，IL-10也能够直接促进记忆性CD 4 + T细胞的存活，因此支持神经元炎症。根据这些看似矛盾的数据，我们的初步研究结果表明，IL-10对不同的T辅助细胞亚群的CNS（中枢神经系统）和肠道之间的影响有重要的差异。基于这些发现，我们假设，IL-10对CD 4 + T细胞有双重作用，这可以是直接和间接的依赖于特定的T辅助细胞亚型以及组织特异性因素。为了验证这一假设，我们将使用肠道和神经炎症的小鼠模型。此外，我们将使用报告基因敲入小鼠模型（Foxp 3 mRFP x Il-10 eGFP x Il-17 a FP 635）和IL-10信号传导受损（Cd 4-dnIL-10 R）或完全消除（条件性IL-10 R α敲除）的转基因小鼠，以特异性分析IL-10信号传导在Foxp 3 + Treg和TH 17细胞中的作用。我们的目的是首先分析是否IL-10/IL-10（R）受体轴的差异调节神经元和肠道炎症的原因。在第二步中，我们将确定IL-10信号传导是否在EAE的诱导和效应阶段在调节TH 17细胞和Foxp 3 + Treg中发挥不同的作用。此外，我们将阐明IL-10在中枢神经系统（CNS）中控制T细胞反应的组织特异性作用。为此，我们将i）研究IL-10对于CNS中Foxp 3 + Treg介导的TH 17细胞的控制的作用，ii）测试Foxp 3 + Treg是否通过IL-10信号传导的正反馈环控制它们在CNS中的活性，和iii）鉴定在CNS中的Foxp 3 +Treg中特异性受IL-10调节的候选基因。这些研究将导致更好地了解IL-10对炎症的调节，并可能为治疗CNS和肠道自身免疫性和慢性炎症性疾病的新组织特异性疗法奠定基础。