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Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3

Nature Immunology volume 14, pages 238–245 (2013)Cite this article

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Abstract

Infection with influenza virus results in the deposition of anti-influenza CD8+ resident memory T cells (TRM cells) in the lung. As a consequence of their location in the lung mucosal tissue, these cells are exposed to cytopathic pathogens over the life of the organism and may themselves be susceptible to infection. Here we found that lung TRM cells selectively maintained expression of the interferon-induced transmembrane protein IFITM3, a protein that confers broad resistance to viral infection. Lung TRM cells that lacked IFITM3 expression were more susceptible to infection than were their normal counterparts and were selectively lost during a secondary bout of infection. Thus, lung TRM cells were programmed to retain IFITM3 expression, which facilitated their survival and protection from viral infection during subsequent exposures.

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Figure 1: Expression and location of IFITM3 in naive and activated CD8+ T cells.
Figure 2: Memory CD8+ T cells in the lungs have high expression of IFITM3 that is dependent on antigen recognition in the tissue.
Figure 3: Virus-specific memory CD8+ T cells persist in the lung parenchyma after intranasal infection with influenza virus and express CD103.
Figure 4: The Ifitm3 promoter is hypomethylated in memory CD8+ T cells.
Figure 5: IFITM3-deficient memory CD8+ T cells are selectively lost during a secondary bout of viral infection.
Figure 6: IFITM3-deficient memory CD8+ T cells are lost during secondary infection with influenza virus.
Figure 7: IFITM3 expression on memory CD8+ T cells enhances resistance to viral infection.

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Acknowledgements

We thank P. Crack (University of Melbourne) and P. Hertzog (Monash Institute of Medical Research) for mice deficient in the receptor for type I interferon; S. Elledge (Harvard Medical School) for the pINDUCER constructs; F. Carbone (University of Melbourne) for the influenza virus flu-OVA (wsn-OVA); S. Turner (University of Melbourne) for the influenza viruses Pr8-OVA and x31-OVA; and A. Brooks (University of Melbourne) for influenza viruses Pr8 and x31. Supported by the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Division of Inflammation, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

    Linda M Wakim, Nishma Gupta, Justine D Mintern & Jose A Villadangos

  2. Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia

    Linda M Wakim & Jose A Villadangos

  3. Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Australia

    Justine D Mintern & Jose A Villadangos

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  1. Linda M Wakim
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  2. Nishma Gupta
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Contributions

L.M.W. and J.A.V. designed the research and wrote the paper; L.M.W. and N.G. did experiments; and J.A.V., J.D.M. and L.M.W. analyzed and interpreted the data.

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Correspondence to Linda M Wakim or Jose A Villadangos.

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Wakim, L., Gupta, N., Mintern, J. et al. Enhanced survival of lung tissue-resident memory CD8+ T cells during infection with influenza virus due to selective expression of IFITM3. Nat Immunol 14, 238–245 (2013). https://doi.org/10.1038/ni.2525

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