IL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection.
IL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection.
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IL-33 诱导胸腺退化相关的幼稚 T 细胞老化并损害宿主对严重感染的控制
DOI：
10.1038/s41467-022-34660-4
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发表时间：
2022-11-12
影响因子：
16.6
通讯作者：
Chen, Xiaojun
中科院分区：
文献类型：
--
作者：
Xu, Lei;Wei, Chuan;Chen, Ying;Wu, Yue;Shou, Xiaoli;Chen, Wenjie;Lu, Di;Sun, Haoran;Li, Wei;Yu, Beibei;Wang, Xiaowei;Zhang, Xiaojun;Yu, Yanxiong;Lei, Zhigang;Tang, Rui;Zhu, Jifeng;Li, Yalin;Lu, Linrong;Zhou, Hong;Zhou, Sha;Su, Chuan;Chen, Xiaojun
严重感染通常会导致免疫抑制，从而导致人类和动物的病原体清除受损或继发感染增加。然而，确切的机制仍然知之甚少。在这里，我们证明 IL-33 通过诱导胸腺退化相关的幼稚 T 细胞功能障碍和衰老相关基因的异常表达而导致免疫抑制，并损害血吸虫病或脓毒症小鼠疾病模型中的宿主对感染的控制。此外，我们还发现 IL-33 以 Pou2f3 依赖性方式触发髓质胸腺上皮细胞 (mTEC) IV（胸腺簇细胞）的过度生成，从而扰乱 mTEC/皮质 TEC (cTEC) 区室并在严重感染期间导致胸腺复旧。更重要的是，IL-33缺陷、抗IL-33中和抗体治疗或IL-33受体ST2缺陷胸腺移植可以挽救T细胞免疫，从而更好地控制小鼠感染。我们的研究结果不仅揭示了严重感染诱导的 IL-33 与胸腺退化介导的幼稚 T 细胞衰老之间的联系，而且还表明靶向 IL-33 或 ST2 是恢复 T 细胞免疫力以更好地控制严重感染的有前途的策略。严重感染导致的免疫抑制会损害病原体的清除，并可能增加继发感染的易感性。在这里，作者剖析了 T 细胞衰老和在此过程中发生的胸腺退化如何导致免疫抑制，并发现 IL-33 的关键作用。
Severe infection commonly results in immunosuppression, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant expression of aging-associated genes and impairs host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrate that IL-33 triggers the excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbs mTEC/cortical TEC (cTEC) compartment and causes thymic involution during severe infection. More importantly, IL-33 deficiency, the anti-IL-33 neutralizing antibody treatment, or IL-33 receptor ST2 deficient thymus transplantation rescues T cell immunity to better control infection in mice. Our findings not only uncover a link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection. Immunosuppression as a result of severe infection impairs pathogen clearance and can increase susceptibility to secondary infection. Here, the authors dissect how T cell aging and the thymic involution that occurs during this process contribute to immunosuppression and find a key role for IL-33.
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影响因子：
1.3
作者：
Danahy DB;Strother RK;Badovinac VP;Griffith TS
通讯作者：
Griffith TS
影响因子：
7.3
作者：
Hams E;Aviello G;Fallon PG
通讯作者：
Fallon PG
影响因子：
5.2
作者：
Kong, Yaxian;Li, Yajie;Zeng, Hui
通讯作者：
Zeng, Hui
滤泡辅助 T 细胞促进日本血吸虫感染期间小鼠的肝脏病理学
影响因子：
6.7
作者：
Chen X;Yang X;Li Y;Zhu J;Zhou S;Xu Z;He L;Xue X;Zhang W;Dong X;Wu H;Li CJ;Hsu HT;Kong W;Liu F;Tripathi PB;Yu MS;Chang J;Zhou L;Su C
通讯作者：
Su C
DOI：
10.1038/nri3667
发表时间：
2014-06
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Klein L;Kyewski B;Allen PM;Hogquist KA
通讯作者：
Hogquist KA