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1.
J Pathol ; 234(2): 164-77, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24797160

ABSTRACT

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 CD11b(high) 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.


Subject(s)
Cardiomyopathies/virology , Enterovirus , Killer Cells, Natural/metabolism , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Animals , CD8-Positive T-Lymphocytes/immunology , Cardiomyopathies/immunology , Cardiomyopathies/pathology , Coxsackievirus Infections/prevention & control , Enterovirus/immunology , Inflammation/immunology , Killer Cells, Natural/immunology , Male , Mice, Inbred C57BL , Myocarditis/etiology , Myocarditis/immunology , Myocardium/pathology , NK Cell Lectin-Like Receptor Subfamily K/immunology
2.
Eur J Immunol ; 43(4): 1024-33, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23401034

ABSTRACT

Adiponectin (APN) has been shown to exert antiinflammatory effects in various disease models but little is known concerning its regulation of NK-cell function. Here, we show that the majority of human CD56(dim) NK cells express surface Adiponectin receptor (AdipoR) 1 and 2 while most CD56(high) NK cells are AdipoR-negative. Toll-like receptor (TLR) ligand-induced IFN-γ production was diminished by APN while it had no influence on NK-cell cytotoxicity. In contrast only a small subpopulation of murine NK cells expresses surface AdipoRs, but about 90% store them intracellularly. APN-deficient knockout (KO) mice had elevated frequencies of NK cells. However, cytotoxic degranulation of NK cells was decreased in APN knockout (APN-KO) animals. Accordingly, frequencies of CD11b(high) CD27(high) and CD94(high) effector NK cells and expression of NKG2D were lower in APN-KO mice. Upon CVB3 infection NK-cell function was restored in APN-KO mice. Our data suggest that in addition to its antiinflammatory effects APN also influences the numerical and differentiation status of NK cells, which may further impact the outcome of immune-mediated diseases in APN-KO mice.


Subject(s)
Adiponectin/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Adiponectin/genetics , Animals , Cell Degranulation/immunology , Cells, Cultured , Cytotoxicity, Immunologic , Gene Expression Regulation , Humans , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Ligands , Mice , Mice, Knockout , Receptors, Adiponectin/genetics , Receptors, Adiponectin/metabolism , Toll-Like Receptors/metabolism
3.
Transpl Int ; 25(3): 302-13, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22188119

ABSTRACT

T-cell-depleting strategies are an integral part of immunosuppressive regimens used in the hematological and solid organ transplant setting. Besides prevention of alloreactivity, treatment with rabbit antithymocyte globulin (rATG) has been related to the induction of immunoregulatory T cells (Treg) in vitro and in vivo. To investigate Treg induced by rATG, we prospectively studied the effect of rATG induction therapy in liver-transplanted recipients in vivo (n = 28). Treg induction was further evaluated by means of Treg-specific demethylation region (TSDR) analysis within the FOXP3 locus. Whereas no induction of CD4(+) CD25(high) CD127(-) Treg could be observed by phenotypic analysis, we could demonstrate an induction of TSDR(+) T cells within CD4(+) T cells exclusively for rATG-treated patients in the long-term (day 540) compared with controls (P = NS). Moreover, although in vitro experiments confirm that rATG primarily led to a conversion of CD4(+) CD25(-) into CD4(+) CD25(+) T cells displaying immunosuppressive capacities, these cells cannot be classified as bona fide Treg based on their FOXP3 demethylation pattern. Consequently, the generation of Treg after rATG co-incubation in vitro does not reflect the mechanisms of Treg induction in vivo and therefore the potential clinical relevance of these cells for transplant outcome remains to be determined.


Subject(s)
Antilymphocyte Serum/immunology , Immunosuppressive Agents/immunology , Liver Transplantation/immunology , Lymphocyte Activation , T-Lymphocytes, Regulatory/metabolism , Transplantation Conditioning/methods , Adult , Animals , Antilymphocyte Serum/therapeutic use , End Stage Liver Disease/surgery , Female , Flow Cytometry , Forkhead Transcription Factors/metabolism , Graft Rejection/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Male , Methylation , Middle Aged , Rabbits , Real-Time Polymerase Chain Reaction , Retrospective Studies
4.
Eur J Heart Fail ; 13(6): 611-8, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21422001

ABSTRACT

AIMS: To quantify and functionally characterize the intramyocardial T-cells in endomyocardial biopsies (EMBs) from patients presenting with acute myocarditis (AMC) and dilated cardiomyopathy (DCM). METHODS AND RESULTS: Expression of genes characterizing Th1 [interferon (IFN)γ, Tbet-1, Eomesodermin, interleukin (IL)-27], Th2 (IL-4, IL-5, GATA3), Th17 (IL-17), regulatory [regulatory T-cells (Treg); FoxP3, TGFß, IL-10], anergic (GRAIL), and cytotoxic T-cells (CTLs: Perforin, Granulysin, Granzyme A), as well as of functional T-cell receptor Vbeta (TRBV) families were investigated in EMBs from AMC patients (n= 58) and DCM patients (n= 34) by pre-amplified real-time reverse transcription-polymerase chain reaction. These data were compared with EMBs from n= 19 controls. Expression of CD3d, CD3z, and TRBC (T-cell receptor beta constant region) were associated with the immunohistological diagnosis of inflammatory cardiomyopathy (DCMi). In EMBs from DCM patients with increased CD3d expression, significantly increased markers of Th1 (IFNγ, T-bet, Eomesodermin), regulatory T-cells (Treg; FoxP3, TGFß), and cytotoxic T-cells (CTLs: Perforin, Granulysin, Granzyme A) were present, while no differential polarization of T-cells was found in EMBs form AMC patients. A differential dominance of distinct functional TRBV families was associated with different cardiotropic viruses: TRBV 11 and 24 with Parvovirus B19; TRBV4, 10 and 28 with human herpes virus type 6; and TRBV14 for Coxsackie virus, respectively. CONCLUSIONS: The T-cell infiltrates in human DCMi are characterized by differential expression of functional T-cell markers indicating Th1, Treg, and CTLs, while no major role could be confirmed for Th17. The virus-associated differential TRBV dominance suggests an antiviral specificity of virus-induced T-cell responses in human DCMi.


Subject(s)
Biomarkers/metabolism , Cardiomyopathy, Dilated/immunology , Myocarditis/immunology , Receptors, Antigen, T-Cell, alpha-beta/metabolism , T-Lymphocytes/metabolism , Acute Disease , Adult , Aged , Biopsy , Cardiomyopathy, Dilated/virology , Endocardium/pathology , Female , Gene Expression , Humans , Male , Middle Aged , Myocarditis/virology , Myocardium/pathology , Receptors, Antigen, T-Cell, alpha-beta/genetics , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction
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