Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity
Hypoxia Enhances Immunosuppression by Inhibiting CD4+ Effector T Cell Function and Promoting Treg Activity
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DOI：
10.1159/000464429
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发表时间：
2017-01-01
影响因子：
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通讯作者：
Jendrossek, Verena
中科院分区：
文献类型：
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作者：
Westendorf, Astrid M.;Skibbe, Kathrin;Jendrossek, Verena
背景/目的：缺氧发生在许多病理条件下，包括炎症和癌症。在这一背景下，低氧被证明抑制但也促进T细胞反应。由于这一有争议的功能，我们的目标是探索结肠炎相关性结肠癌期间抗肿瘤反应不足是否可归因于低氧微环境。方法：用野生型小鼠建立结肠炎相关结肠癌模型，对肿瘤组织进行缺氧和T细胞免疫分析。此外，在常氧和低氧条件下培养CD4(+)效应T细胞和调节性T细胞，并检测其表型和功能。结果：我们观察到结肠炎相关性结肠癌小鼠的结肠严重缺氧，伴随着CD4(+)效应T细胞分化减少，调节性T细胞数量和抑制活性增加。体外和体外互补研究表明，低氧条件下T细胞刺激抑制T(H)1细胞的分化、增殖和干扰素-γ的产生，并增强调节性T细胞的抑制能力。此外，我们发现HIF-1α在低氧条件下对CD4(+)T细胞功能的调节中起着积极的作用。结论：我们的数据表明，氧气供应可以作为CD4(+)T细胞反应的局部调节器发挥作用，从而影响炎症相关性结肠癌的肿瘤免疫监测。(C)2017作者(S)发稿：S卡格尔股份公司，巴塞尔
Background/Aims: Hypoxia occurs in many pathological conditions, including inflammation and cancer. Within this context, hypoxia was shown to inhibit but also to promote T cell responses. Due to this controversial function, we aimed to explore whether an insufficient anti-tumour response during colitis-associated colon cancer could be ascribed to a hypoxic microenvironment. Methods: Colitis-associated colon cancer was induced in wildtype mice, and hypoxia as well as T cell immunity were analysed in the colonic tumour tissues. In addition, CD4(+) effector T cells and regulatory T cells were cultured under normoxic and hypoxic conditions and examined regarding their phenotype and function. Results: We observed severe hypoxia in the colon of mice suffering from colitis-associated colon cancer that was accompanied by a reduced differentiation of CD4(+) effector T cells and an enhanced number and suppressive activity of regulatory T cells. Complementary ex vivo and in vitro studies revealed that T cell stimulation under hypoxic conditions inhibited the differentiation, proliferation and IFN-gamma production of T(H)1 cells and enhanced the suppressive capacity of regulatory T cells. Moreover, we identified an active role for HIF-1 alpha in the modulation of CD4(+) T cell functions under hypoxic conditions. Conclusion: Our data indicate that oxygen availability can function as a local modulator of CD4(+) T cell responses and thus influences tumour immune surveillance in inflammation-associated colon cancer. (C) 2017 The Author(s) Published by S Karger AG, Basel