Oncotarget

Research Papers: Pathology:

The NKG2D – IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies

Tobias Ruck _, Stefan Bittner, Ali Maisam Afzali, Kerstin Göbel, Sarah Glumm, Peter Kraft, Claudia Sommer, Christoph Kleinschnitz, Corinna Preuße, Werner Stenzel, Heinz Wiendl and Sven G. Meuth

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Oncotarget. 2015; 6:43230-43243. https://doi.org/10.18632/oncotarget.6462

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Abstract

Tobias Ruck1, Stefan Bittner2, Ali Maisam Afzali1, Kerstin Göbel1, Sarah Glumm1, Peter Kraft3, Claudia Sommer3, Christoph Kleinschnitz3, Corinna Preuße4, Werner Stenzel4, Heinz Wiendl1,* and Sven G. Meuth1,*

1 Department of Neurology, University of Muenster, Muenster, Germany

2 Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

3 Department of Neurology, University Hospital of Wuerzburg, Wuerzburg, Germany

4 Department of Neuropathology, Charité-Universitätsmedizin, Berlin, Germany

* These authors have contributed equally to this work

Correspondence to:

Tobias Ruck, email:

Keywords: NKG2D, IL-15, polymyositis, idiopathic inflammatory myopathies, T cell activation, Pathology Section

Received: June 08, 2015 Accepted: November 14, 2015 Published: December 04, 2015

Abstract

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 naïve CD8+ T cells into highly activated, cytotoxic CD8+NKG2Dhigh T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. CD8+NKG2Dhigh 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.


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