IL-15 Participates in the Respiratory Innate Immune Response to Influenza Virus Infection

Katherine C Verbist,Mary B Field,Charles J Cole,Kimberly D Klonowski,David L Rose,George Kassiotis

doi:10.1371/journal.pone.0037539

Abstract

Following influenza infection, natural killer (NK) cells function as interim effectors by suppressing viral replication until CD8 T cells are activated, proliferate, and are mobilized within the respiratory tract. Thus, NK cells are an important first line of defense against influenza virus. Here, in a murine model of influenza, we show that virally-induced IL-15 facilitates the trafficking of NK cells into the lung airways. Blocking IL-15 delays NK cell entry to the site of infection and results in a disregulated control of early viral replication. By the same principle, viral control by NK cells can be therapeutically enhanced via intranasal administration of exogenous IL-15 in the early days post influenza infection. In addition to controlling early viral replication, this IL-15-induced mobilization of NK cells to the lung airways has important downstream consequences on adaptive responses. Primarily, depletion of responding NK1.1+ NK cells is associated with reduced immigration of influenza-specific CD8 T cells to the site of infection. Together this work suggests that local deposits of IL-15 in the lung airways regulate the coordinated innate and adaptive immune responses to influenza infection and may represent an important point of immune intervention.

Highlights

Influenza virus is a major human pathogen that causes substantial morbidity and mortality—approximately 36,000 deaths annually in the United States alone [1]
Because this interleukin 15 (IL-15) expression was rapidly induced by influenza infection and reached significant levels as early as day 3 post infection (p.i.) [19], we hypothesized that influenza-induced IL-15 expression may be an important mediator of natural killer (NK) cell responses to influenza infection
Lymphocytes were isolated from the lung airways of influenzainfected animals via bronchioalveolar lavage (BAL), and CD32, NK1.1+ NK cells were analyzed for the expression of IL-15 receptor components by flow cytometry

Summary

Introduction

Influenza virus is a major human pathogen that causes substantial morbidity and mortality—approximately 36,000 deaths annually in the United States alone [1]. Influenza virus is primarily transmitted via inhaled aerosols and results in an infection localized to the upper respiratory tract, with viral replication largely limited to epithelial cells [3]. Mechanisms by which the immune system eliminates influenza have been well studied and are known to involve the coordinated actions of the innate and adaptive immune systems. The cytolytic action of influenza-specific CD8 T cells has been shown to be the primary mediator of complete viral clearance, but important roles have been described for CD4 T cells [4,5,6]. NK cells are vital in limiting influenza viral replication as depletion of NK cells dramatically increases morbidity and mortality in hamsters and mice [9], and in humans severe infections with the 2009 pandemic

Methods

Results

Conclusion