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IRF4-dependent dendritic cells regulate CD8+ T-cell differentiation and memory responses in influenza infection

Mucosal Immunology (2019) | Download Citation

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Abstract

Acute respiratory disease caused by influenza viruses is imperfectly mitigated by annual vaccination to select strains. Development of vaccines that elicit lung-resident memory CD8+ T cells (TRM) would offer more universal protection to seasonal and emerging pandemic viruses. Understanding how lung-resident dendritic cells (DCs) regulate TRM differentiation would be an important step in this process. Here, we used CD11c-cre-Irf4f/f (KO) mice, which lack lung-resident IRF4-dependent CD11b+CD24hi DCs and show IRF4 deficiency in other lung cDC subsets, to determine if IRF4-expressing DCs regulate CD8+ memory precursor cells and TRM during influenza A virus (IAV) infection. KO mice showed defective CD8+ T-cell memory, stemming from a deficit of T regulatory cells and memory precursor cells with decreased Foxo1 expression. Transfer of wild-type CD11b+CD24hi DCs into KO mice restored CD8+ memory precursor cell numbers to wild-type levels. KO mice recovered from a primary infection harbored reduced numbers of CD8+ TRM and showed deficient expansion of IFNγ+CD8+ T cells and increased lung pathology upon challenge with heterosubtypic IAV. Thus, vaccination strategies that harness the function of IRF4-dependent DCs could promote the differentiation of CD8+ TRM during IAV infection.

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Acknowledgements

We thank Dr. Gillian Air and Shelly Gulati at OUHSC for assistance with growing and titering virus in eggs, Dr. Diana Hamilton and Jacob Bass in the OMRF Flow Cytometry Core Facility, and the staff of the Comparative Medicine Facility. This work was supported by NIH HL119501 (to S. Kovats) and by an OMRF Patricia and Don Capra Predoctoral Fellowship (to S. Kadel).

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Affiliations

  1. Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA

    • Erola Ainsua-Enrich
    • , Ibrahim Hatipoglu
    • , Sapana Kadel
    • , Sean Turner
    • , Jinny Paul
    • , Simar Singh
    • , Harini Bagavant
    •  & Susan Kovats
  2. Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    • Sapana Kadel
    •  & Susan Kovats

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Contributions

E.A.-E. designed and performed experiments, analyzed data and wrote the manuscript. I.H. and H.B. designed and performed experiments and analyzed data. S. Kadel, S.T., J.P. and S.S. performed experiments. S. Kovats conceived of the study, designed experiments, analyzed data and wrote the manuscript.

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The authors declare no competing interests.

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Correspondence to Susan Kovats.

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https://doi.org/10.1038/s41385-019-0173-1