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Vaccine-induced antigen-specific regulatory T cells attenuate the antiviral immunity against acute influenza virus infection

Mucosal Immunologyvolume 11pages12391253 (2018) | Download Citation

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Abstract

Peptide-based T cell vaccines targeting the conserved epitopes of influenza virus can provide cross-protection against distantly related strains, but they are generally not immunogenic. Foreign antigen-specific regulatory T (Treg) cells are induced under subimmunogenic conditions peripherally, although their development and role in vaccine-mediated antiviral immunity is unclear. Here, we demonstrated primary vaccination with peptides alone significantly induced antigen-specific Foxp3+ Treg cells, which were further expanded by repeated vaccination with unadjuvanted peptides. Certain adjuvants, including CpG, suppressed the induction and expansion of antigen-specific Treg cells by peptide vaccination. Interestingly, secondary influenza virus infection significantly increased the frequency of preexisting antigen-specific Treg cells, although primary infection barely induced them. Importantly, specific depletion of vaccine-induced antigen-specific Treg cells promoted influenza viral clearance, indicating their inhibitory role in vivo. Immunization with CpG-adjuvanted peptides by the subcutaneous prime–intranasal-boost strategy restricted the recruitment and accumulation of antigen-specific Treg cells in lung, and stimulated robust T cell immunity. Finally, subcutaneous prime–intranasal-boost immunization with CpG-adjuvanted peptides or whole-inactivated influenza vaccines protected mice from heterosubtypic influenza virus infection. In conclusion, antigen-specific Treg cells induced by peptide vaccines attenuate the antiviral immunity against influenza virus infection. CpG-adjuvanted peptide vaccines provide heterosubtypic influenza protection probably by inhibiting Treg development and enhancing T cell immunity.

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Acknowledgements

We thank Dr. Mi-Hua Tao and Dr. Ching-Hwa Tsai for their critical review and constructive comments on this manuscript. We also would like to acknowledge the service provided by the Flow Cytometric Analyzing and Sorting Core of the First Core Laboratory and the Third Core Laboratory, National Taiwan University College of Medicine. This work was supported by grants from the National Taiwan University Hospital (grant number UN106-057), and the Ministry of Science and Technology (grant number MOST105-2628-B-002-027-MY3), Executive Yuan, Taiwan.

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Affiliations

  1. Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan

    • Pin-Hung Lin
    • , Weng-In Wong
    • , Yi-Lan Wang
    • , Meng-Ping Hsieh
    • , Chia-wen Lu
    • , Chieh-Yu Liang
    • , Sung-Hsiang Jui
    • , Fang-Yi Wu
    •  & Hung-Chih Yang
  2. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

    • Pei-Jer Chen
    •  & Hung-Chih Yang
  3. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    • Pei-Jer Chen
    •  & Hung-Chih Yang
  4. Hepatitis Research Center, , National Taiwan University Hospital, Taipei, Taiwan

    • Pei-Jer Chen

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Contributions

P.-H.L. P.-J.C., and H.-C.Y. formed the original concepts and designs of the experiments. P.-H.L., W.-I.W., Y.-L.W., M.-P.H., C.-W.L., C.-Y.L., and S.-H.J. performed the experiments; P.-H.L. acquired and interpreted data; P.-J.C and H.-C.Y. reviewed and helped interpret the data; P.-H.L. and H.-C.Y. drafted and finalized the submitted manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Hung-Chih Yang.

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https://doi.org/10.1038/s41385-018-0004-9

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