title: Skeletal muscle interleukin 15 promotes CD8(+) T-cell function and autoimmune myositis.
abstract: BACKGROUND
  Interleukin 15 (IL-15) is thought to be abundant in the skeletal muscle under steady state conditions based on RNA expression; however, the IL-15 RNA level may not reflect the protein level due to post-transcriptional regulation. Although exogenous protein treatment and overexpression studies indicated IL-15 functions in the skeletal muscle, how the skeletal muscle cell uses IL-15 remains unclear. In myositis patients, IL-15 protein is up-regulated in the skeletal muscle. Given the supporting role of IL-15 in CD8(+) T-cell survival and activation and the pathogenic role of cytotoxic CD8(+) T cells in polymyositis and inclusion-body myositis, we hypothesize that IL-15 produced by the inflamed skeletal muscle promotes myositis via CD8(+) T cells.
  
  
  METHODS
  Expression of IL-15 and IL-15 receptors at the protein level by skeletal muscle cells were examined under steady state and cytokine stimulation conditions. The functions of IL-15 in the skeletal muscle were investigated using Il15 knockout (Il15 (-/-) ) mice. The immune regulatory role of skeletal muscle IL-15 was determined by co-culturing cytokine-stimulated muscle cells and memory-like CD8(+) T cells in vitro and by inducing autoimmune myositis in skeletal-muscle-specific Il15 (-/-) mice.
  
  
  RESULTS
  We found that the IL-15 protein was not expressed by skeletal muscle cells under steady state condition but induced by tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) stimulation and expressed as IL-15/IL-15 receptor alpha (IL-15Rα) complex. Skeletal muscle cells expressed a scanty amount of IL-15 receptor beta (IL-15Rβ) under either conditions and only responded to a high concentration of IL-15 hyperagonist, but not IL-15. Consistently, deficiency of endogenous IL-15 affected neither skeletal muscle growth nor its responses to TNF-α and IFN-γ. On the other hand, the cytokine-stimulated skeletal muscle cells presented antigen and provided IL-15 to promote the effector function of memory-like CD8(+) T cells. Genetic ablation of Il15 in skeletal muscle cells greatly ameliorated autoimmune myositis in mice.
  
  
  CONCLUSIONS
  These findings together indicate that skeletal muscle IL-15 directly regulates immune effector cells but not muscle cells and thus presents a potential therapeutic target for myositis.
authors.affiliation: Molecular Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica, and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan ; Institute of Molecular Biology, Academia Sinica, Taipei, 11529 Taiwan.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Huang
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, 11529 Taiwan.
authors.forename: Mau-Sheng
authors.initials: MS
authors.lastname: Hou
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, 11529 Taiwan.
authors.forename: Szu-Wen
authors.initials: SW
authors.lastname: Wang
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, 11529 Taiwan.
authors.forename: Chin-Ling
authors.initials: CL
authors.lastname: Chang
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, 11529 Taiwan.
authors.forename: Yae-Huei
authors.initials: YH
authors.lastname: Liou
authors.affiliation: Molecular Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica, and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan ; Institute of Molecular Biology, Academia Sinica, Taipei, 11529 Taiwan.
authors.forename: Nan-Shih
authors.initials: NS
authors.lastname: Liao
keywords: Autoimmune myositis; CD8+ T cell; IL-15; Skeletal muscle