2. Academic Validation
  3. 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

  • Nat Commun. 2022 Nov 12;13(1):6881. doi: 10.1038/s41467-022-34660-4.
Lei Xu # 1 2 3 4 5 6,  Chuan Wei # 1 2 3 4,  Ying Chen 1 2 3 4,  Yue Wu 1 2 3 4,  Xiaoli Shou 1 2 3 4,  Wenjie Chen 1 2 3 4,  Di Lu 1 2 3 4,  Haoran Sun 1 2 3 4,  Wei Li 6,  Beibei Yu 1 2 3 4,  Xiaowei Wang 7,  Xiaojun Zhang 8,  Yanxiong Yu 1 2 3 4,  Zhigang Lei 1 2 3 4,  Rui Tang 1 2 3 4,  Jifeng Zhu 1 2 3 4,  Yalin Li 1 2 3 4,  Linrong Lu 9,  Hong Zhou 10,  Sha Zhou 11 12 13 14,  Chuan Su 15 16 17 18,  Xiaojun Chen 19 20 21 22
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China.
  • 2 State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China.
  • 3 Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China.
  • 4 Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China.
  • 5 Department of Respiratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, P. R. China.
  • 6 Department of Clinical Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, P. R. China.
  • 7 Department of Blood Transfusion, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210008, P. R. China.
  • 8 Imaging Center, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210008, P. R. China.
  • 9 Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, 310058, P. R. China.
  • 10 Department of Cell Biology, School of Life Sciences, Anhui Medical University, Hefei, 230032, P. R. China.
  • 11 Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. shazhou@njmu.edu.cn.
  • 12 State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. shazhou@njmu.edu.cn.
  • 13 Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. shazhou@njmu.edu.cn.
  • 14 Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. shazhou@njmu.edu.cn.
  • 15 Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. chuansu@njmu.edu.cn.
  • 16 State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. chuansu@njmu.edu.cn.
  • 17 Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. chuansu@njmu.edu.cn.
  • 18 Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. chuansu@njmu.edu.cn.
  • 19 Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. chenxiaojun@njmu.edu.cn.
  • 20 State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. chenxiaojun@njmu.edu.cn.
  • 21 Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. chenxiaojun@njmu.edu.cn.
  • 22 Center for Global Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, P. R. China. chenxiaojun@njmu.edu.cn.
  • # Contributed equally.
PMID: 36371464 DOI: 10.1038/s41467-022-34660-4
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.

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