Control of pro-inflammatory TH17 cells in the small intestine

CD4+ T辅助细胞在调节免疫应答中发挥重要作用。不同类型的调节性T细胞具有免疫抑制或抗炎特性。研究最多的两个亚群是Foxp3+调节性T细胞（Foxp3+ Treg）和T调节性1型细胞（Tr1）。相反，存在不同亚型的效应CD4+ T辅助细胞（如TH1、TH2、TH17），它们是促炎性的。这些促炎性T辅助细胞对于抵抗微生物是必不可少的。然而，如果不加控制，它们可能导致慢性炎症和自身免疫性疾病。 这些效应T辅助细胞的一种亚型，TH17细胞特别与慢性炎症和自身免疫性疾病相关。然而，TH17细胞对于防御细胞外细菌和真菌也至关重要。因此，控制这些促炎性TH17细胞的内源性机制似乎是至关重要的。我们最近发现了这样一种内源性机制：我们可以证明，例如在脓毒症期间发生的压倒性TH17免疫应答诱导TH17细胞选择性募集到小肠。有趣的是，TH17可以在那一侧控制。部分促炎性TH17细胞被冲洗到肠腔中，而剩余的TH17细胞由Tr1和Foxp3+ Treg细胞控制。最后，这些TH17获得了具有体外和体内免疫抑制特性的调节表型（rTH17）。因此，TH17细胞可以在促炎和抗炎表型之间切换，这使它们成为免疫调节疗法的非常有吸引力的靶标。 该项目的目的是分析这种控制TH17细胞的内源性机制。这些研究有助于发展自身免疫性疾病和慢性炎症性疾病的新治疗策略。

CD4+ T helper cells play an essential role in regulating the immune response. Different types of regulatory T cells have immune suppressive or anti-inflammatory properties. The two most studied subsets are Foxp3+ regulatory T cells (Foxp3+ Treg) and T regulatory type 1 cells (Tr1). On the contrary there are different subtypes of effector CD4+ T helper cells (like TH1, TH2, TH17) which are pro-inflammatory. These pro-inflammatory T helper cells are essential for the defense against micro-organismen. However, if uncontrolled they can cause chronic inflammation and autoimmune disease. One subtype of these effector T helper cells, TH17 cells is particularly associated with chronic inflammatory and autoimmune diseases. However TH17 cells are also crucial for the defense against extra cellular bacteria and fungi. Therefore an endogenous mechanisms controlling these pro-inflammatory TH17 cells seems to be crucial. We recently identified such an endogenous mechanism: We could demonstrate that an overwhelming TH17 immune response, which occurs for example during sepsis, induces a selective recruitment of TH17 cells to the small intestine. Interestingly TH17 could be controlled at that side. Part of the pro-inflammatory TH17 cells was washed out into the intestinal lumen, while the remaining TH17 cells were controlled by Tr1 and Foxp3+ Treg cells. Finally these TH17 acquired a regulatory phenotype (rTH17) with in vitro and in vivo immune suppressive properties. Therefore TH17 cells can switch between a pro- and an anti-inflammatory phenotype, which makes them a very attractive target for immune regulatory therapies. The aim of the proposed project is to analyze this endogenous mechanism controlling TH17 cells. These studies can contribute to the development of new therapeutic strategies for autoimmune and chronic inflammatory diseases.