The CD4+ T Cell-Mediated IFN-γ Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk
The CD4+ T Cell-Mediated IFN-γ Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk
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DOI：
10.4049/jimmunol.0803293
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发表时间：
2009-06-01
影响因子：
4.4
通讯作者：
Mueller, Anne
中科院分区：
文献类型：
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作者：
Sayi, Ayca;Kohler, Esther;Mueller, Anne
细菌病原体幽门螺杆菌的慢性感染是胃癌发展的危险因素，但大多数人仍然无症状。我们在此报告，用密切相关的猫螺杆菌实验感染的 C5713L/6 小鼠模型概括了宿主易感性的这种广泛范围。尽管大多数受感染的动物会出现癌前病变，例如胃萎缩、代偿性上皮增生和肠化生，但仍有一部分小鼠完全免受癌前病变的影响。保护作用与未能对感染产生 IFN-γ 反应以及随之而来的高螺杆菌负荷有关。使用疫苗模型以及原发感染和过继转移模型，我们证明主要由CD4（+）CD25（-）效应T-H细胞分泌的IFN-γ对于螺杆菌的清除至关重要，但同时介导肿瘤前病变的形成。我们进一步提供证据表明，IFN-γ在体外和体内触发小鼠胃上皮细胞中的常见转录程序，并诱导其优先转化为增生表型。总之，我们的数据表明 IFN-γ 在幽门螺杆菌发病机制中的双重作用，这可能是人类对幽门螺杆菌引起的胃病理学的不同易感性的基础。免疫学杂志，2009，182：7085-7101。
Chronic infection with the bacterial pathogen Helicobacter pylori is a risk factor for the development of gastric cancer, yet remains asymptomatic in the majority of individuals. We report here that the C5713L/6 mouse model of experimental infection with the closely related Helicobacter felis recapitulates this wide range in host susceptibility. Although the majority of infected animals develop premalignant lesions such as gastric atrophy, compensatory epithelial hyperplasia, and intestinal metaplasia, a subset of mice is completely protected from preneoplasia. Protection is associated with a failure to mount an IFN-gamma response to the infection and with a concomitant high Helicobacter burden. Using a vaccine model as well as primary infection and adoptive transfer models, we demonstrate that IFN-gamma, secreted predominantly by CD4(+)CD25(-) effector T-H cells, is essential for Helicobacter clearance, but at the same time mediates the formation of preneoplastic lesions. We further provide evidence that IFN-gamma triggers a common transcriptional program in murine gastric epithelial cells in vitro and in vivo and induces their preferential transformation to the hyperplastic phenotype. In summary, our data suggest a dual role for IFN-gamma in Helicobacter pathogenesis that could be the basis for the differential susceptibility to H. pylori-induced gastric pathology in the human population. The Journal of Immunology, 2009, 182: 7085-7101.