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Pulmonary immunization with a recombinant influenza A virus vaccine induces lung-resident CD4+ memory T cells that are associated with protection against tuberculosis

Mucosal Immunologyvolume 11pages17431752 (2018) | Download Citation

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Abstract

The lung is the primary site of infection with the major human pathogen, Mycobacterium tuberculosis. Effective vaccines against M. tuberculosis must stimulate memory T cells to provide early protection in the lung. Recently, tissue-resident memory T cells (TRM) were found to be phenotypically and transcriptional distinct from circulating memory T cells. Here, we identified M. tuberculosis-specific CD4+ T cells induced by recombinant influenza A viruses (rIAV) vaccines expressing M. tuberculosis peptides that persisted in the lung parenchyma with the phenotypic and transcriptional characteristics of TRMs. To determine if these rIAV-induced CD4+ TRM were protective independent of circulating memory T cells, mice previously immunized with the rIAV vaccine were treated with the sphingosine-1-phosphate receptor modulator, FTY720, prior to and during the first 17 days of M. tuberculosis challenge. This markedly reduced circulating T cells, but had no effect on the frequency of M. tuberculosis-specific CD4+ TRMs in the lung parenchyma or their cytokine response to infection. Importantly, mice immunized with the rIAV vaccine were protected against M. tuberculosis infection even when circulating T cells were profoundly depleted by the treatment. Therefore, pulmonary immunization with the rIAV vaccine stimulates lung-resident CD4+ memory T cells that are associated with early protection against tuberculosis infection.

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Acknowledgements

This work was supported by the National and Medical Research Council of Australia through Project Grant APP1044343, and the Center of Research Excellence in TB Control (APP1043225), and the NSW Government through its infrastructure grant to the Centenary Institute. H.M. was a recipient of Australia Award Scholarship from the Australian Department of Foreign Affairs and Trade.

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Affiliations

  1. Tuberculosis Research Program, Centenary Institute, The University of Sydney, Newtown, NSW, Australia

    • Manuela Flórido
    • , Heni Muflihah
    • , Leon C. W. Lin
    • , Mainthan Palendira
    • , Carl G. Feng
    • , James A. Triccas
    •  & Warwick. J. Britton
  2. School of Medicine, Deakin University, Geelong, VIC, Australia

    • Yingju Xia
    •  & John Stambas
  3. Liver Immunology Program, Centenary Institute, The University of Sydney, Newtown, NSW, Australia

    • Frederic Sierro
    •  & Patrick Bertolino
  4. Department of Pathology, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

    • Frederic Sierro
  5. Department of Infectious Diseases and Immunology, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

    • Mainthan Palendira
    • , Carl G. Feng
    • , James A. Triccas
    •  & Warwick. J. Britton
  6. AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

    • Patrick Bertolino
  7. Department of Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

    • Warwick. J. Britton

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Contributions

M.F., H.M. and L.L designed and performed experiments, and M.F, wrote the manuscript. Y.X. developed the rIAV vaccines under supervision of J.S. F.S. assisted with 2-photon microscopy experiments. M.P., C.F., P.B. and J.A.T. contributed to the experimental design and provided intellectual input. W.B. was responsible for study design, data interpretation, and study supervision. All the authors contributed to the editing of the manuscript.

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The authors declare no competing interests.

Corresponding author

Correspondence to Warwick. J. Britton.

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DOI

https://doi.org/10.1038/s41385-018-0065-9