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.
Highlights
Idiopathic inflammatory myopathies are a heterogeneous group of muscle disorders characterized by chronic muscle inflammation and progressive muscle weakness
As a prerequisite for muscle cell-specific, NKG2D-dependent pathology in inflammatory myopathies we investigated the NKG2D ligand expression on primary human myoblasts under basal and inflammatory conditions
We found a significant downregulation of NKG2D ligand shedding ADAMs (A Disintegrin and Metalloproteinase) 9, 10 and 17 [34] in human myoblasts by IFNγ plus TNFα treatment (Figure 1C) corroborating previous findings demonstrating diminished ADAM9, ADAM10, ADAM17 and ADAM19 gene expression in myoblasts under pro-inflammatory stimuli in vitro [35]
Summary
Idiopathic inflammatory myopathies are a heterogeneous group of muscle disorders characterized by chronic muscle inflammation and progressive muscle weakness. New insights into the pathogenesis of idiopathic inflammatory myopathies have identified muscle-resident CD4+ and CD8+ T cells in PM, DM and IBM as predominantly CD28null T cells. In the case of CD4+CD28null cells, the fundamental differences to conventional CD4+ T helper cells are obvious and underline the need to reevaluate the local immunological milieu in the inflamed muscle tissue that drives and maintains T cell functions [8]. In this context, muscle cells and myoblasts actively shape (auto) immune reactions as they secrete inflammatory cytokines and chemokines or express costimulatory molecules [911]
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