The activating receptor NKG2D of natural killer cells promotes resistance against enterovirus-mediated inflammatory cardiomyopathy

In enterovirus‐induced cardiomyopathy, information regarding the detailed impact of natural killer (NK) cells on the outcome of the disease is limited. We therefore hypothesized that NK cells and certain NK cell receptors determine the different outcome of coxsackievirus B3 (CVB3) myocarditis. Here,...

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Published inThe Journal of pathology Vol. 234; no. 2; pp. 164 - 177
Main Authors Klingel, Karin, Fabritius, Cornelia, Sauter, Martina, Göldner, Katrin, Stauch, Diana, Kandolf, Reinhard, Ettischer, Nicole, Gahlen, Sabine, Schönberger, Tanja, Ebner, Susanne, Makrigiannis, Andrew P, Bélanger, Simon, Diefenbach, Andreas, Polić, Bojan, Pratschke, Johann, Kotsch, Katja
Format Journal Article
LanguageEnglish
Published Chichester, UK John Wiley & Sons, Ltd 01.10.2014
Wiley Subscription Services, Inc
Subjects
Animals
Cardiomyopathies - immunology
Cardiomyopathies - pathology
Cardiomyopathies - virology
CD8-Positive T-Lymphocytes - immunology
Coxsackievirus B3
Coxsackievirus Infections - prevention & control
Enterovirus - immunology
Inflammation - immunology
Killer Cells, Natural - immunology
Killer Cells, Natural - metabolism
Male
Mice, Inbred C57BL
Myocarditis - etiology
Myocarditis - immunology
Myocardium - pathology
natural killer cells
NK Cell Lectin-Like Receptor Subfamily K - immunology
NK Cell Lectin-Like Receptor Subfamily K - metabolism
NKG2D
virus-induced cardiomyopathy
natural killer cells
virus-induced cardiomyopathy
NKG2D
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Summary:In enterovirus‐induced cardiomyopathy, information regarding the detailed impact of natural killer (NK) cells on the outcome of the disease is limited. We therefore hypothesized that NK cells and certain NK cell receptors determine the different outcome of coxsackievirus B3 (CVB3) myocarditis. Here, we demonstrate in murine models that resistance to chronic CVB3 myocarditis in immunocompetent C57BL/6 mice is characterized by significantly more mature CD11bhigh NK cells, the presence of NKG2D on NK cells, and enhanced NKG2D‐dependent cytotoxicity compared to CVB3‐susceptible A.BY/SnJ mice. The highly protective role of NKG2D in myocarditis was further proven by in vivo neutralization of NKG2D as well as in NKG2D‐deficient mice but was shown to be independent of CD8+ T‐cell‐dependent immunity. Moreover, the adoptive transfer of immunocompetent C57BL/6 NK cells pre‐ (day −1) as well as post‐infectionem (day +2) displayed the potential to prevent permissive A.BY/SnJ mice from a progressive outcome of CVB3 myocarditis reflected by significantly improved cardiopathology and heart function. Altogether, our results provide firm evidence for a protective role of NKG2D‐activated NK cells in CVB3 myocarditis leading to an effective virus clearance, thus offering novel therapeutic options in the treatment of virus‐induced myocarditis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
Bibliography:Supplementary materials and methods.Figure S1. Tracking of transferred NKp46+ PKH26+ NK cells derived from C57BL/6 mice in various tissues of CVB3-infected A.BY/SnJ mice.Figure S2. Cytotoxicity and activation of NK cells derived from C57BL/6 (*) and A.BY/SnJ (□) mice.Figure S3. (A) Histology and immunohistochemistry for the visualization of myocardial damage, T-cell and macrophage infiltration at day 8 p.i. after NK cell transfer (day −1) in the control groups: NKG2D-deficient NK cells into A.BY/SnJ and C57BL/6 mice, as well as C57BL/6-derived NK cells transferred into C57BL/6 mice. (B) Detection of virus replication (VP1) staining at day 8 p.i. in NK cell-transferred control groups compared with A.BY/SnJ and C57BL/6 wild-type mice. Magnification × 180. (C) Quantification of myocardial damage and virus replication in n = 5-6 animals/group. Transfer of NK cells prior to infection (day −1) from NKG2D-deficient mice to A.BY/SnJ or to C57BL/6 mice did not change the cardiac phenotype of the animals with regard to virus replication or myocardial damage and inflammation (compare Figures and for images of infected control mice).Figure S4. Age-dependent maturation of splenic NK cells derived from C57BL/6 (*) and A.BY/SnJ (□) mice.Figure S5. NKG2DL expression, cytotoxicity, and activation of NK cells derived from C57BL/6 (*) and A.BY/SnJ (□) mice.Figure S6. mRNA expression of RIG-1, MDA5, and TLR3 in the myocardium derived from naïve and CVB3-infected C57BL/6 (*) and A.BY/SnJ (□) mice.Figure S7. IFNγ mRNA expression in spleen and heart derived from naïve and CVB3-infected C57BL/6 (*) and NKG2D-deficient mice (○).Table S1. Primers for real-time RT-PCR.
ark:/67375/WNG-9340T3HP-M
ArticleID:PATH4369
Deutsche Stiftung für Herzforschung
Deutsche Forschungsgemeinschaft - No. (SFB/TR 19, TP B4 and Z4)
istex:20B3A0A844A949157EEF4A34BDD568EED0839AE7
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-3417
1096-9896
DOI:10.1002/path.4369