Influenza A Virus Infection Induces Hyperresponsiveness in Human Lung Tissue-Resident and Peripheral Blood NK Cells

Marlena Scharenberg,Anna Färnert,Eliisa Kekäläinen,Per Bergman,Anna Smed-Sörensen,Sindhu Vangeti,Hans-Gustaf Ljunggren,Sara Falck-Jones,Mamdoh Al-Ameri,Niclas Johansson,Nicole Marquardt,Jakob Michaëlsson,Klara Sondén

doi:10.3389/fimmu.2019.01116

Marlena Scharenberg, Anna Färnert + Show 11 more

Open Access

https://doi.org/10.3389/fimmu.2019.01116

Copy DOI

Abstract

NK cells in the human lung respond to influenza A virus- (IAV-) infected target cells. However, the detailed functional capacity of human lung and peripheral blood NK cells remains to be determined in IAV and other respiratory viral infections. Here, we investigated the effects of IAV infection on human lung and peripheral blood NK cells in vitro and ex vivo following clinical infection. IAV infection of lung- and peripheral blood-derived mononuclear cells in vitro induced NK cell hyperresponsiveness to K562 target cells, including increased degranulation and cytokine production particularly in the CD56brightCD16− subset of NK cells. Furthermore, lung CD16− NK cells showed increased IAV-mediated but target cell-independent activation compared to CD16+ lung NK cells or total NK cells in peripheral blood. IAV infection rendered peripheral blood NK cells responsive toward the normally NK cell-resistant lung epithelial cell line A549, indicating that NK cell activation during IAV infection could contribute to killing of surrounding non-infected epithelial cells. In vivo, peripheral blood CD56dimCD16+ and CD56brightCD16− NK cells were primed during acute IAV infection, and a small subset of CD16−CD49a+CXCR3+ NK cells could be identified, with CD49a and CXCR3 potentially promoting homing to and tissue-retention in the lung during acute infection. Together, we show that IAV respiratory viral infections prime otherwise hyporesponsive lung NK cells, indicating that both CD16+ and CD16− NK cells including CD16−CD49a+ tissue-resident NK cells could contribute to host immunity but possibly also tissue damage in clinical IAV infection.

Highlights

Acute respiratory infections cause 4 million deaths every year [1]
natural killer (NK) cells are the most frequent innate lymphoid cells in human lung tissue [3], and the vast majority of NK cells in the human lung are circulating between the organ and perhipheral blood [3]
Respiratory virus infections such as Influenza A virus (IAV) and respiratory syncytial virus (RSV) are likely to affect NK cells residing in the lung and NK cells in the circulation or cells circulating between the lung and peripheral blood

Summary

Introduction

Acute respiratory infections cause 4 million deaths every year [1]. Of these, infection with seasonal influenza and other respiratory viruses such as respiratory syncytial virus (RSV) constitute a major clinical and economic burden. Apart from the general respiratory symptoms, a major complication during different stages of respiratory viral infection is the severe tissue damage affecting the lung The latter is caused by the viral infection and replication in target cells per se, and by influx of and immunological reactions by immune cells including lymphocytes in the lung affecting non-infected cells. An influenza-specific adaptive-like NK cell subset has been shown to be present in mouse liver but not the lung following infection [8] Both in mice and in humans, a hallmark of hepatic adaptive-like NK cells is high expression of CD49a [9, 10], which is a hallmark for trNK cells in diverse compartments including the human lung [2, 11] (Marquardt et al, unpublished observations)

Methods

Results

Conclusion