Respiratory DC Use IFITM3 to Avoid Direct Viral Infection and Safeguard Virus-Specific CD8+ T Cell Priming

Giuseppe Infusini; Jeffrey M Smith; He Yuan; Angela Pizzolla; Wy Ching Ng; Sarah L Londrigan; Ashraful Haque; Patrick C Reading; Jose A Villadangos; Linda M Wakim

doi:10.1371/journal.pone.0143539

Respiratory DC Use IFITM3 to Avoid Direct Viral Infection and Safeguard Virus-Specific CD8+ T Cell Priming

PLoS One. 2015 Nov 23;10(11):e0143539. doi: 10.1371/journal.pone.0143539. eCollection 2015.

Authors

Affiliations

¹ Division of Systems Biology and Personalised Medicine, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
² Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
³ Malaria Immunology Lab, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁴ WHO Collaborating Centre for Reference and Research on Influenza, Victorian Infectious Diseases Reference Laboratory, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
⁵ Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.

Abstract

Respiratory dendritic cells (DC) play a pivotal role in the initiation of adaptive immune responses to influenza virus. To do this, respiratory DCs must ferry viral antigen from the lung to the draining lymph node without becoming infected and perishing en route. We show that respiratory DCs up-regulate the expression of the antiviral molecule, interferon-induced transmembrane protein 3 (IFITM3) in response to influenza virus infection, in a manner dependent on type I interferon signaling and the transcription factors IRF7 and IRF3. Failure of respiratory DCs to up-regulate IFITM3 following influenza virus infection resulted in impaired trafficking to the draining LN and consequently in impaired priming of an influenza-specific CD8+ T cell response. The impaired trafficking of IFITM3-deficient DC correlated with an increased susceptibility of these DC to influenza virus infection. This work shows that the expression of IFITM3 protects respiratory DCs from influenza virus infection, permitting migration from lung to LN and optimal priming of a virus specific T-cell response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
Cells, Cultured
Dendritic Cells / metabolism*
Flow Cytometry
Interferon Regulatory Factor-3 / metabolism
Interferon Regulatory Factor-7 / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Knockout
Orthomyxoviridae Infections / immunology*
Orthomyxoviridae Infections / metabolism

Substances

Interferon Regulatory Factor-3
Interferon Regulatory Factor-7
Irf3 protein, mouse
Irf7 protein, mouse
Membrane Proteins
fragilis protein, mouse

Grants and funding

This work was funded by the National Health and Medical Research Council (NHMRC) of Australia, with additional support from the University of Melbourne (Early Career Establishment Grant) and Bio21 Institute/CSL Ltd. J. A. Villadangos is a NHMRC Principal Research Fellow and L. Wakim is a NHMRC Career Development Fellow. The Melbourne WHO Collaborating Centre for Reference and Research on Influenza is supported by the Australian Government Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.