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

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有关。因此，IL-10可以作用于抗原提呈细胞并抑制其成熟，从而间接控制CD4+ t细胞应答。此外，我们和其他人最近报道了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（Foxp3+Treg），促进其抑制功能，从而间接控制TH17细胞。此外，IL-10还可以直接与TH17细胞相互作用，从而控制其表型和扩增。相反，在多发性硬化症（实验性自身免疫性脑脊髓炎（EAE））小鼠模型中显示，IL-10也能够直接促进记忆性CD4+ T细胞的存活，从而支持神经元炎症。与这些看似矛盾的数据一致，我们的初步结果表明，IL-10对中枢神经系统和肠道之间不同T辅助细胞亚群的影响存在重要差异。基于这些发现，我们假设IL-10对CD4+ T细胞具有双重作用，可以直接或间接地取决于特定的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，我们将使用敲入小鼠模型（Foxp3 mRFP x Il-10 eGFP x Il-17a FP635）和受损（Cd4-dnIL-10R）或完全消除Il-10信号（条件IL-10R α敲除）的转基因小鼠，以特异性分析Il-10信号在Foxp3+ Treg和TH17细胞中的作用。我们的目的是首先分析IL-10/IL-10(R)受体轴是否在神经元和肠道炎症的原因中受到差异调节。在第二步中，我们将确定IL-10信号在EAE诱导和效应阶段是否在调节TH17细胞和Foxp3+ Treg中发挥差异作用。此外，我们将阐明IL-10在中枢神经系统（CNS）中控制t细胞反应中的组织特异性作用。为此，我们将i)研究IL-10在Foxp3+Treg介导的中枢神经系统TH17细胞调控中的作用，ii)测试Foxp3+Treg是否通过IL-10信号的正反馈回路控制其在中枢神经系统中的活性，iii)确定IL-10在中枢神经系统中特异性调节Foxp3+Treg的候选基因。这些研究将有助于更好地理解IL-10对炎症的调节，并可能为治疗中枢神经系统和肠道的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。

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.