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Antigen-presenting innate lymphoid cells induced by BCG vaccination promote a respiratory antiviral immune response through the skin‒lung axis

Cellular & Molecular Immunology volume 22, pages 390–402 (2025)Cite this article

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Abstract

The route of vaccine administration is associated with various immune outcomes, and the relationship between the route of administration and broad protection against heterologous pathogens remains unclear. Here, we found that subcutaneous vaccination with Bacillus Calmette-Guérin (BCG) promotes respiratory influenza clearance and T-cell responses. Group 1 innate lymphoid cells (ILC1s) express MHCII molecules and engage in antigen processing and presentation after BCG vaccination. During influenza virus infection, ILC1s in the lungs of BCG-vaccinated mice can present influenza virus antigens and prime Th1 cells. After subcutaneous vaccination with BCG, MHCII+ ILC1s migrate from the skin to the lungs and play an antigen-presenting role in influenza infection. Both the BCG and the BCG component lipomannan can induce MHCII expression and skin-to-lung migration of ILC1s via TLR2 signaling. Our study revealed an important regulatory mechanism by which subcutaneous vaccination with BCG promotes respiratory antiviral immune responses via the skin‒lung axis.

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Data availability

All data, including raw sequencing data, have been deposited at the National Genomics Data Center under accession number: CRA022270 (https://ngdc.cncb.ac.cn/).

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Acknowledgements

We thank Prof. George F Gao (Institute of Microbiology, Chinese Academy of Sciences) for providing the influenza A/Puerto Rico/8/34 (H1N1, PR8) virus strain. We thank Prof. Cuihua Liu (Institute of Microbiology, Chinese Academy of Sciences) for providing Bacillus Calmette-Guérin (BCG). We thank Prof. Zongfang Li (Xi’an Jiaotong University, China) for providing KikGR mice. We thank Prof. Pengyan Xia and Qiannv Liu (Peking University, China) for their technical support. We thank Dr. Tong Zhao and Dr. Jingfang Liu (Institute of Microbiology, Chinese Academy of Sciences) for their technical support. We thank Prof. Changyong Tian (Technical Institute of Physics and Chemistry, Chinese Academy of Sciences) for providing the 405 nm laser. This work was supported by the National Key R&D Program of China (2022YFC2302900, 2021YFA1300202, 2023YFC2306204), the Beijing Natural Science Foundation (JQ24043), and the CAS Project for Young Scientists in Basic Research (YSBR-010). The cartoons in Figs. 1a, 3c, f, 4a, 5b, 5f and the supplementary information Fig. S7 were created with BioRender.com.

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Authors and Affiliations

  1. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China

    Dou Yu, Xintong Gao, Fei Shao, Zhen Liu, Aoyi Liu, Min Zhao, Zhuozhou Tang, Yude Guan & Shuo Wang

  2. University of Chinese Academy of Sciences, 100049, Beijing, China

    Dou Yu, Xintong Gao, Fei Shao, Zhen Liu, Aoyi Liu, Zhuozhou Tang, Yude Guan & Shuo Wang

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DY performed the experiments and analyzed the data; XG, FS, ZL, AL, MZ, ZT, and YG performed the experiments; SW initiated the study and organized, designed, and wrote the paper.

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Correspondence to Shuo Wang.

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Yu, D., Gao, X., Shao, F. et al. Antigen-presenting innate lymphoid cells induced by BCG vaccination promote a respiratory antiviral immune response through the skin‒lung axis. Cell Mol Immunol 22, 390–402 (2025). https://doi.org/10.1038/s41423-025-01267-w

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