NK cells are activated and primed for skin-homing during acute dengue virus infection in humans

Christine L Zimmer,Mei Qiu Lim,Laura Rivino,Martin A Ivarsson,Niklas K Björkström,Paul A Macary,Carles Solà-Riera,David Chien Lye,Nicole Marquardt,Hans-Gustaf Ljunggren,Martin Cornillet,Jonas Klingström,Ka-Wai Cheung,Yee-Sin Leo

doi:10.1038/s41467-019-11878-3

Abstract

Despite animal models showing that natural killer (NK) cells are important players in the early defense against many viral infections, the NK cell response is poorly understood in humans. Here we analyze the phenotype, temporal dynamics, regulation and trafficking of NK cells in a patient cohort with acute dengue virus infection. NK cells are robustly activated and proliferate during the first week after symptom debut. Increased IL-18 levels in plasma and in induced skin blisters of DENV-infected patients, as well as concomitant signaling downstream of the IL-18R, suggests an IL-18-dependent mechanism in driving the proliferative NK cell response. Responding NK cells have a less mature phenotype and a distinct chemokine-receptor imprint indicative of skin-homing. A corresponding NK cell subset can be localized to skin early during acute infection. These data provide evidence of an IL-18-driven NK cell proliferation and priming for skin-homing during an acute viral infection in humans.

Highlights

Despite animal models showing that natural killer (NK) cells are important players in the early defense against many viral infections, the NK cell response is poorly understood in humans
A similar pattern of activation marker expression was seen for CD69 as well as for CD38, the latter depicted as median fluorescence intensity (MFI), albeit with lower percentages of CD69 expression on CD56bright NK cells during the acute phase of infection (Fig. 1c, d)
While the expression of the anti-apoptotic molecule Bcl-2 was observed to be slightly down-regulated in responding CD56bright and CD56dim NK cells (Fig. 2b, d–f), the downregulation was modest in magnitude compared to the downregulation of Bcl-2 observed in responding T cells from the same patients (Fig. 2e, f)

Summary

Introduction

Despite animal models showing that natural killer (NK) cells are important players in the early defense against many viral infections, the NK cell response is poorly understood in humans. A corresponding NK cell subset can be localized to skin early during acute infection. These data provide evidence of an IL-18-driven NK cell proliferation and priming for skin-homing during an acute viral infection in humans. It is known that NK cells participate in the control of acute infections by many different viruses[3,4] In humans, their importance is underscored in rare NK cell deficiencies, resulting in a high susceptibility to many viral and other infections[5]. Many details are missing with respect to how an early NK cell response to an acute viral infection is driven in humans. NK cells are activated by cytokines such as type I interferons, interleukin-12 (IL-12), IL-15, and IL-181–3

Methods

Results

Conclusion