TY  - JOUR
A1  - Ruck, Tobias
A1  - Bittner, Stefan
A1  - Afzali, Ali Maisam
A1  - Göbel, Kerstin
A1  - Glumm, Sarah
A1  - Kraft, Peter
A1  - Sommer, Claudia
A1  - Kleinschnitz, Christoph
A1  - Preusse, Corinna
A1  - Stenzel, Werner
A1  - Wiendl, Heinz
A1  - Meuth, Sven G.
T1  - The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies
JF  - Oncotarget
N2  - NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naive CD8\(^+\) T cells into highly activated, cytotoxic \(CD8^+NKG2D^{high}\) T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. \(CD8^+NKG2D^{high}\) T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68\(^+\) macrophages as well as CD4\(^+\) T cells, and \(CD8^+NKG2D^+\) cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues.
KW  - MIC ligands
KW  - pathology section
KW  - T cell activation
KW  - idiopathic inflammatory myopathies
KW  - polymyositis
KW  - IL-15
KW  - NKG2D
KW  - receptor
KW  - expression
KW  - lymphokine-activated killer
KW  - human muscle-cells
KW  - multiple sclerosis
KW  - celiac disease
KW  - tumor immunity
KW  - NKG2D ligands
KW  - cutting edge
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136047
VL  - 6
IS  - 41
ER  - 
TY  - JOUR
A1  - Køllgaard, Tania
A1  - Ugurel-Becker, Selma
A1  - Idorn, Manja
A1  - Andersen, Mads Hald
A1  - Becker, Jürgen C.
A1  - Straten, Per thor
T1  - Pre-Vaccination Frequencies of Th17 Cells Correlate with Vaccine-Induced T-Cell Responses to Survivin-Derived Peptide Epitopes
JF  - PLoS One
N2  - Various subsets of immune regulatory cells are suggested to influence the outcome of therapeutic antigen-specific anti-tumor vaccinations. We performed an exploratory analysis of a possible correlation of pre-vaccination Th17 cells, MDSCs, and Tregs with both vaccination-induced T-cell responses as well as clinical outcome in metastatic melanoma patients vaccinated with survivin-derived peptides. Notably, we observed dysfunctional Th1 and cytotoxic T cells, i.e. down-regulation of the CD3\(\zeta\)chain (p=0.001) and an impaired IFN\(\gamma\)-production (p=0.001) in patients compared to healthy donors, suggesting an altered activity of immune regulatory cells. Moreover, the frequencies of Th17 cells (p=0.03) and Tregs (p=0.02) were elevated as compared to healthy donors. IL-17-secreting CD4\(^{+}\) T cells displayed an impact on the immunological and clinical effects of vaccination: Patients characterized by high frequencies of Th17 cells at pre-vaccination were more likely to develop survivin-specific T-cell reactivity post-vaccination (p=0.03). Furthermore, the frequency of Th17 (p=0.09) and Th17/IFN\(\gamma\)\(^{+}\) (p=0.19) cells associated with patient survival after vaccination. In summary, our explorative, hypothesis-generating study demonstrated that immune regulatory cells, in particular Th17 cells, play a relevant role for generation of the vaccine-induced anti-tumor immunity in cancer patients, hence warranting further investigation to test for validity as predictive biomarkers.
KW  - suppressor cells
KW  - melanoma patients
KW  - patient survival
KW  - cancer patients
KW  - Th17
KW  - tumor immunity
KW  - blood
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151509
VL  - 10
IS  - 7
ER  -