Abstract

Virus infection induces the development of T follicular helper (TFH) and T helper 1 (TH1) cells. Although TFH cells are important in anti-viral humoral immunity, the contribution of TH1 cells to a protective antibody response remains unknown. We found that IgG2 antibodies predominated in the response to vaccination with inactivated influenza A virus (IAV) and were responsible for protective immunity to lethal challenge with pathogenic H5N1 and pandemic H1N1 IAV strains, even in mice that lacked TFH cells and germinal centers. The cytokines interleukin-21 and interferon-γ, which are secreted from TH1 cells, were essential for the observed greater persistence and higher titers of IgG2 protective antibodies. Our results suggest that TH1 induction could be a promising strategy for producing effective neutralizing antibodies against emerging influenza viruses.

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Acknowledgements

We thank Y. Ito and A. Komano for helpful advice about the IAV infection experiments. We thank Y. Harada, Y. Motomura, H. Fujimoto, Y. Hachiman and Y. Suzuki for technical support and animal maintenance. We thank P. Burrows for helpful comments on the manuscript. We thank B. Malissen (CIML) for the Cd3e-deficient mice. This work was supported by a Grant-in-Aid for Scientific Research (A) (24249058) to M.K., and by Takeda Science Foundation, Uehara Foundation and The Naito Foundation.

Author information

Affiliations

  1. Laboratory for Cytokine Regulation, Research Center for Integrative Medical Science (IMS), RIKEN Yokohama Institute, Yokohama, Japan.

    • Kosuke Miyauchi
    • , Yoshiko Usami
    •  & Masato Kubo
  2. Drug Discovery Antibody Platform Unit, IMS, RIKEN Yokohama Institute, Yokohama, Japan.

    • Akiko Sugimoto-Ishige
    • , Tomohiro Kaji
    •  & Toshitada Takemori
  3. Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, Noda, Japan.

    • Yasuyo Harada
    •  & Masato Kubo
  4. Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.

    • Yu Adachi
    •  & Yoshimasa Takahashi
  5. Biological Research Department, Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd, Tokyo, Japan.

    • Tomohiro Kaji
  6. Laboratory for Integrated Cellular Systems, IMS, RIKEN Yokohama Institute, Yokohama, Japan.

    • Kentaro Inoue
    •  & Mariko Okada-Hatakeyama
  7. Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.

    • Hideki Hasegawa
  8. Laboratory for Integrative Genomics, IMS, RIKEN Yokohama Institute, Yokohama, Japan.

    • Takashi Watanabe
    •  & Osamu Ohara
  9. Department of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan.

    • Atsushi Hijikata
  10. Division of Virology, Department of Microbiology and Immunology and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

    • Satoshi Fukuyama
    • , Tadashi Maemura
    •  & Yoshihiro Kawaoka
  11. Influenza Research Institute, University of Wisconsin-Madison, Madison, Wisconsin, USA.

    • Satoshi Fukuyama
    •  & Yoshihiro Kawaoka
  12. ERATO Infection-induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.

    • Yoshihiro Kawaoka

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Contributions

K.M. and M.K. designed and conceptualized the research and analyzed the data. A.S.-I., Y.H., Y.U., T.K., Y.T. and K.M. performed H1N1 experiments. K.M., S.F., T.M. and Y.K. performed H5N1 experiments. T.W., A.H. and O.O. performed Ig sequencing analysis. K.I. and M.O.-H. performed statistical data analysis of RNA sequencing. H.H., Y.A. and Y.T. established and provided H1N1 Narita virus. T.T. established the Bcl6fl/fl mice. M.K. established the Il21fl/fl mice, and the Il4, Il21 and Ifng reporter mice. K.M., M.K. and T.T. prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Masato Kubo.

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https://doi.org/10.1038/ni.3563

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