ILC3s promote intestinal tuft cell hyperplasia and anthelmintic immunity through RANK signaling

  • Sci Immunol. 2025 May 16;10(107):eadn1491. doi: 10.1126/sciimmunol.adn1491.
Hongkai Xu  1  2  3 ,  Yibo Wang  1  2  3  4 ,  Wenyan Wang  2  4 ,  Yang-Xin Fu  2  4 ,  Ju Qiu  5 ,  Yan Shi  1  2  3 ,  Lei Yuan  1 ,  Chen Dong  6 ,  Xiaoyu Hu  1  2  3 ,  Ye-Guang Chen  7 ,  Xiaohuan Guo  1  2  3  4  8
Affiliations
  • 1. Institute for Immunology, Tsinghua University, Beijing 100084, China.
  • 2. School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing 100084, China.
  • 3. Beijing Key Laboratory of Immunological Research of Allergy (LIRA), Tsinghua University, Beijing 100084, China.
  • 4. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
  • 5. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 6. Westlake University, Hangzhou 310030, China.
  • 7. State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 8. SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
PMID: 40378237 DOI: 10.1126/sciimmunol.adn1491
Abstract

Helminth infections, particularly in developing countries, remain a notable health burden worldwide. Group 3 innate lymphoid cells (ILC3s) are enriched in the intestine and play a critical role in immunity against extracellular bacteria and fungi. However, whether ILC3s are involved in intestinal helminth Infection is still unclear. Here, we report that helminth Infection reprograms ILC3s, which, in turn, promote anthelmintic immunity. ILC3-derived RANKL [receptor activator of NF-κB (nuclear factor κB) ligand] synergizes with interleukin-13 (IL-13) to facilitate intestinal tuft cell expansion after helminth Infection, which further activates the tuft cell-group 2 innate lymphoid cell (ILC2) circuit to control helminth Infection. Deletion of RANKL in ILC3s or deletion of RANK or its downstream adaptor RelB in intestinal epithelial cells substantially diminishes tuft cell hyperplasia and dampens anthelmintic immunity. Thus, ILC3s play an indispensable role in protecting against helminth Infection through the regulation of intestinal tuft cell hyperplasia and type 2 immunity.

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