Dengue Virus-Infected Dendritic Cells, but Not Monocytes, Activate Natural Killer Cells through a Contact-Dependent Mechanism Involving Adhesion Molecules.

Vivian Vasconcelos Costa,Jianzhu Chen,Weijian Ye,Qingfeng Chen,Mauro Martins Teixeira,Eng Eong Ooi,Peter Preiser,Peter Palese

doi:10.1128/mbio.00741-17

Abstract

ABSTRACTNatural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood. Using an optimized humanized mouse model, we show that human NK cells, through the secretion of gamma interferon (IFN-γ), are critical in the early defense against DENV infection. Depletion of NK cells or neutralization of IFN-γ leads to increased viremia and more severe thrombocytopenia and liver damage in humanized mice. In vitro studies using autologous human NK cells show that DENV-infected monocyte-derived dendritic cells (MDDCs), but not monocytes, activate NK cells in a contact-dependent manner, resulting in upregulation of CD69 and CD25 and secretion of IFN-γ. Blocking adhesion molecules (LFA-1, DNAM-1, CD2, and 2β4) on NK cells abolishes NK cell activation, IFN-γ secretion, and the control of DENV replication. NK cells activated by infected MDDCs also inhibit DENV infection in monocytes. These findings show the essential role of human NK cells in protection against acute DENV infection in vivo, identify adhesion molecules and dendritic cells required for NK cell activation, and delineate the sequence of events for NK cell activation and protection against DENV infection.

Highlights

Natural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood
Blocking all four adhesion molecules simultaneously did not result in an additive effect on the reduction of viral titers. These results show that adhesion molecules but not specific natural cytotoxicity receptors are required for NK cell interaction with infected monocytederived dendritic cells (MDDCs), consistent with a requirement for cell-cell contact for NK cell activation, IFN-␥ secretion, and control of DENV infection
We showed that cell-cell contact between infected MDDCs and NK cells is critical for NK cell activation and IFN-␥ secretion

Summary

Introduction

Natural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood. Using a coculture system of monocyte-derived dendritic cells (MDDCs) and autologous human NK cells, it was reported that a combination of cell-cell contact and the secretion of type I interferon and tumor necrosis factor alpha (TNF-␣) by DENV-infected MDDCs (iMDDCs) was required for NK cell activation, secretion of IFN-␥, and cytotoxicity toward iMDDCs [18]. Despite these findings, how NK cells become activated during DENV infection and what molecules are involved in NK cell activation have not been fully elucidated

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