Systems modeling of the role of interleukin-21 in the maintenance of effector CD4+ T cell responses during chronic Helicobacter pylori infection.
Systems modeling of the role of interleukin-21 in the maintenance of effector CD4+ T cell responses during chronic Helicobacter pylori infection.
复制标题
白介素21在慢性幽门螺杆菌感染过程中维持效应子CD4+ T细胞反应中的作用的系统建模。
DOI：
10.1128/mbio.01243-14
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发表时间：
2014-07-22
期刊：
影响因子：
6.4
通讯作者：
Algood HM
中科院分区：
文献类型：
--
作者：
Carbo A;Olivares-Villagómez D;Hontecillas R;Bassaganya-Riera J;Chaturvedi R;Piazuelo MB;Delgado A;Washington MK;Wilson KT;Algood HM
幽门螺杆菌感染期间胃炎的发展依赖于由T辅助细胞（Th）协调的活化的适应性免疫应答。然而，Th 1和Th 17亚群对胃炎和感染控制的相对贡献仍在研究中。为了研究白细胞介素-21（IL-21）在幽门螺杆菌感染过程中胃粘膜中的作用，我们将CD 4 + T细胞分化的数学模型与体内机制研究相结合。我们用幽门螺杆菌菌株SS 1感染IL-21缺陷型和野生型小鼠，并评估定植、胃炎症、细胞浸润和细胞因子谱。慢性幽门螺杆菌感染的IL-21缺陷小鼠具有更高的幽门螺杆菌定植，显著减少胃炎，并减少促炎细胞因子和趋化因子的表达相比，这些参数在感染的野生型同窝仔。这些体内数据用于校准幽门螺杆菌感染依赖性、CD 4 + T细胞特异性计算模型，该模型随后描述了慢性幽门螺杆菌感染期间IL-21激活干扰素γ（IFN-γ）和IL-17产生的机制。该模型预测了T-bet和RORγt的活化表达以及STAT 3和STAT 1的磷酸化，并提示IL-21在IL-10的调节中的潜在作用。在我们的模型预测的驱动下，我们发现在幽门螺杆菌感染的IL-21缺陷小鼠中，CD 4+脾细胞特异性tbx 21和rorc表达水平降低，STAT 1和STAT 3磷酸化水平降低，CD 4 + T细胞特异性IL-10表达增加。我们的研究结果表明，IL-21调节Th 1和Th 17效应反应在慢性幽门螺杆菌感染中的STAT 1和STAT 3依赖的方式，因此发挥主要作用控制幽门螺杆菌感染和胃炎。幽门螺杆菌是世界上超过50%的人口中胃微生物群的主要成员。幽门螺杆菌定植与胃炎和胃癌有关，因为幽门螺杆菌感染是胃癌最常见的单一风险因素。目前的数据表明，除了细菌毒力因子外，免疫应答的大小和类型也会影响定植和慢性感染的结果。本研究采用计算和实验相结合的方法来研究IL-21，一种促炎性T细胞衍生的细胞因子，如何在幽门螺杆菌感染期间维持慢性促炎性T细胞免疫应答驱动慢性胃炎。这项研究还将深入了解IL-21越来越被认为发挥核心作用的无数其他感染性和免疫性疾病。使用IL-21相关疗法可能为慢性幽门螺杆菌定植的个体提供治疗选择，作为侵袭性抗生素的替代方案。
The development of gastritis during Helicobacter pylori infection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and control of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa during H. pylori infection, we combined mathematical modeling of CD4+ T cell differentiation with in vivo mechanistic studies. We infected IL-21-deficient and wild-type mice with H. pylori strain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. Chronically H. pylori-infected IL-21-deficient mice had higher H. pylori colonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. These in vivo data were used to calibrate an H. pylori infection-dependent, CD4+ T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-γ) and IL-17 during chronic H. pylori infection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of IL-21 in the modulation of IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4+ splenocyte-specific tbx21 and rorc expression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4+ T cell-specific IL-10 expression in H. pylori-infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronic H. pylori infection in a STAT1- and STAT3-dependent manner, therefore playing a major role controlling H. pylori infection and gastritis. Helicobacter pylori is the dominant member of the gastric microbiota in more than 50% of the world’s population. H. pylori colonization has been implicated in gastritis and gastric cancer, as infection with H. pylori is the single most common risk factor for gastric cancer. Current data suggest that, in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization and chronic infection. This study uses a combined computational and experimental approach to investigate how IL-21, a proinflammatory T cell-derived cytokine, maintains the chronic proinflammatory T cell immune response driving chronic gastritis during H. pylori infection. This research will also provide insight into a myriad of other infectious and immune disorders in which IL-21 is increasingly recognized to play a central role. The use of IL-21-related therapies may provide treatment options for individuals chronically colonized with H. pylori as an alternative to aggressive antibiotics.