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

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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.

Abstract

Here, Zimmer et al. analyze the natural killer (NK) cell response in a patient cohort with acute dengue virus infection showing early NK cell activation and proliferation, and the data suggest that NK cell proliferation depends on IL-18 signaling, and that responding NK cells have a skin-homing phenotype.

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Most cited references 42

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Up on the tightrope: natural killer cell activation and inhibition.

Lewis L Lanier (2008)

Natural killer (NK) cells circulate through the blood, lymphatics and tissues, on patrol for the presence of transformed or pathogen-infected cells. As almost all NK cell receptors bind to host-encoded ligands, signals are constantly being transmitted into NK cells, whether they interact with normal or abnormal cells. The sophisticated repertoire of activating and inhibitory receptors that has evolved to regulate NK cell activity ensures that NK cells protect hosts against pathogens, yet prevents deleterious NK cell-driven autoimmune responses. Here I highlight recent advances in our understanding of the structural properties and signaling pathways of the inhibitory and activating NK cell receptors, with a particular focus on the ITAM-dependent activating receptors, the NKG2D-DAP10 receptor complexes and the CD244 receptor system.

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Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education.

Niklas Björkström, Peggy Riese, Frank Heuts … (2010)

Natural killer (NK) cells are lymphocytes of the innate immune system that, following differentiation from CD56(bright) to CD56(dim) cells, have been thought to retain fixed functional and phenotypic properties throughout their lifespan. In contrast to this notion, we here show that CD56(dim) NK cells continue to differentiate. During this process, they lose expression of NKG2A, sequentially acquire inhibitory killer cell inhibitory immunoglobulin-like receptors and CD57, change their expression patterns of homing molecules, and display a gradual decline in proliferative capacity. All cellular intermediates of this process are represented in varying proportions at steady state and appear, over time, during the reconstitution of the immune system, as demonstrated in humanized mice and in patients undergoing hematopoietic stem cell transplantation. CD56(dim) NK-cell differentiation, and the associated functional imprint, occurs independently of NK-cell education by interactions with self-human leukocyte antigen class I ligands and is an essential part of the formation of human NK-cell repertoires.

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Interleukin‐18: Biological properties and role in disease pathogenesis

Gilles Kaplanski (2017)

Summary Initially described as an interferon (IFN)γ‐inducing factor, interleukin (IL)‐18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL‐17‐producing γδ T cells and macrophage activation. IL‐18, a member of the IL‐1 family, is similar to IL‐1β for being processed by caspase 1 to an 18 kDa‐biologically active mature form. IL‐18 binds to its specific receptor (IL‐18Rα, also known as IL‐1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL‐18Rβ chain. IL‐18 then uses the same signaling pathway as IL‐1 to activate NF‐kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL‐18 also binds to the circulating high affinity IL‐18 binding protein (BP), such as only unbound free IL‐18 is active. IL‐18Rα may also bind IL‐37, another member of the IL‐1 family, but in association with the negative signaling chain termed IL‐1R8, which transduces an anti‐inflammatory signal. IL‐18BP also binds IL‐37 and this acts as a sink for the anti‐inflammatory properties of IL‐37. There is now ample evidence for a role of IL‐18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL‐18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain‐of‐function mutations, IL‐18 circulates in the range of tens of nanograms/mL. HS is treated with the IL‐1 Receptor antagonist (anakinra) but also specifically with IL‐18BP. Systemic juvenile idiopathic arthritis or adult‐onset Still's disease are also characterized by high serum IL‐18 concentrations and are treated by IL‐18BP.

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Author and article information

Contributors

Niklas K. Björkström:

ORCID: http://orcid.org/0000-0002-0967-076X

niklas.bjorkstrom@ki.se

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 29 August 2019

Publication date PMC-release: 29 August 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 3897

Affiliations

[1 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, , Karolinska University Hospital, ; Stockholm, Sweden

[2 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Programme in Emerging Infectious Diseases, , DUKE-NUS Medical School, ; Singapore, Singapore

[3 ]GRID grid.240988.f, Institute of Infectious Diseases and Epidemiology, Communicable Disease Centre, , Tan Tock Seng Hospital, ; Singapore, Singapore

[4 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Saw Swee Hock School of Public Health, , National University of Singapore, ; Singapore, Singapore

[5 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Yong Loo Lin School of Medicine, , National University of Singapore, ; Singapore, Singapore

[6 ]ISNI 0000 0001 2224 0361, GRID grid.59025.3b, Lee Kong Chian School of Medicine, , Nanyang Technological University, ; Singapore, Singapore

[7 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Immunology Programme, Life Science Institute and Department of Microbiology and Immunology, , National University of Singapore, ; Singapore, Singapore

[8 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, School of Cellular and Molecular Medicine, , University of Bristol, ; Bristol, UK

Author information

Nicole Marquardt http://orcid.org/0000-0003-3186-4752

David Chien Lye http://orcid.org/0000-0003-0324-0205

Jonas Klingström http://orcid.org/0000-0001-9076-1441

Niklas K. Björkström http://orcid.org/0000-0002-0967-076X

Article

Publisher ID: 11878

DOI: 10.1038/s41467-019-11878-3

PMC ID: 6715742

PubMed ID: 31467285

SO-VID: 6d212240-8b07-4b1e-9de7-c14b9186deb0

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 11 April 2018

Date accepted : 8 August 2019

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ScienceOpen disciplines: Uncategorized

Keywords: interleukins,viral infection,innate lymphoid cells,signal transduction

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ScienceOpen disciplines: Uncategorized

Keywords: interleukins, viral infection, innate lymphoid cells, signal transduction

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

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Decoding Infection and Transmission

Most cited references 42

Up on the tightrope: natural killer cell activation and inhibition.

Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education.

Interleukin‐18: Biological properties and role in disease pathogenesis

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