IL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection

Lei Xu, Chuan Wei, Ying Chen, Yue Wu, Xiaoli Shou, Wenjie Chen, Di Lu, Haoran Sun, Wei Li, Beibei Yu, Xiaowei Wang, Xiaojun Zhang, Yanxiong Yu, Zhigang Lei, Rui Tang, Jifeng Zhu, Yalin Li, Linrong Lu, Hong Zhou, Sha Zhou (), Chuan Su () and Xiaojun Chen ()
Additional contact information
Lei Xu: Nanjing Medical University
Chuan Wei: Nanjing Medical University
Ying Chen: Nanjing Medical University
Yue Wu: Nanjing Medical University
Xiaoli Shou: Nanjing Medical University
Wenjie Chen: Nanjing Medical University
Di Lu: Nanjing Medical University
Haoran Sun: Nanjing Medical University
Wei Li: Nanjing Medical University
Beibei Yu: Nanjing Medical University
Xiaowei Wang: Children’s Hospital of Nanjing Medical University
Xiaojun Zhang: Children’s Hospital of Nanjing Medical University
Yanxiong Yu: Nanjing Medical University
Zhigang Lei: Nanjing Medical University
Rui Tang: Nanjing Medical University
Jifeng Zhu: Nanjing Medical University
Yalin Li: Nanjing Medical University
Linrong Lu: Zhejiang University
Hong Zhou: Anhui Medical University
Sha Zhou: Nanjing Medical University
Chuan Su: Nanjing Medical University
Xiaojun Chen: Nanjing Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34660-4

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