Differential Induction of IFN-α and Modulation of CD112 and CD54 Expression Govern the Magnitude of NK Cell IFN-γ Response to Influenza A Viruses

Lisa M Kronstad, Christof Seiler, Rosemary Vergara, Susan P Holmes, Catherine A Blish

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

In human and murine studies, IFN-γ is a critical mediator immunity to influenza. IFN-γ production is critical for viral clearance and the development of adaptive immune responses, yet excessive production of IFN-γ and other cytokines as part of a cytokine storm is associated with poor outcomes of influenza infection in humans. As NK cells are the main population of lung innate immune cells capable of producing IFN-γ early in infection, we set out to identify the drivers of the human NK cell IFN-γ response to influenza A viruses. We found that influenza triggers NK cells to secrete IFN-γ in the absence of T cells and in a manner dependent upon signaling from both cytokines and receptor-ligand interactions. Further, we discovered that the pandemic A/California/07/2009 (H1N1) strain elicits a seven-fold greater IFN-γ response than other strains tested, including a seasonal A/Victoria/361/2011 (H3N2) strain. These differential responses were independent of memory NK cells. Instead, we discovered that the A/Victoria/361/2011 influenza strain suppresses the NK cell IFN-γ response by downregulating NK-activating ligands CD112 and CD54 and by repressing the type I IFN response in a viral replication-dependent manner. In contrast, the A/California/07/2009 strain fails to repress the type I IFN response or to downregulate CD54 and CD112 to the same extent, which leads to the enhanced NK cell IFN-γ response. Our results indicate that influenza implements a strain-specific mechanism governing NK cell production of IFN-γ and identifies a previously unrecognized influenza innate immune evasion strategy.

Original languageEnglish
Pages (from-to)2117-2131
Number of pages15
JournalJournal of Immunology
Volume201
Issue number7
DOIs
Publication statusPublished - 1 Oct 2018
Externally publishedYes

Keywords

  • CYTOKINE
  • EPITHELIAL-CELLS
  • IN-VIVO
  • INFECTED-CELLS
  • INNATE IMMUNE-RESPONSE
  • MASS CYTOMETRY
  • MEDIATED LYSIS
  • NATURAL-KILLER-CELLS
  • NS1 PROTEIN
  • PANDEMIC INFLUENZA

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