Human muscle cells express the costimulatory molecule B7‐H3, which modulates muscle–immune interactions

Abstract

Objective. Interactions between the family of B7 ligands and their receptors are increasingly recognized as crucial for stimulation and/or inhibition of immune responses. The present study was undertaken to examine the expression and functional relevance of B7 homolog 3 (B7-H3), a novel B7 homolog attributed significant immunoregulatory functions, in human muscle cells in vivo and in vitro.Methods. Thirty-five muscle biopsy specimens obtained from patients with polymyositis, dermatomyositis, inclusion body myositis, or noninflammatory myopathies and normal controls were analyzed by immunohistochemistry for B7-H3 expression. The expression of B7-H3 protein on primary human myoblasts and TE671 muscle rhabdomyosarcoma cells was studied by flow cytometry and Western blot analysis. B7-H3 small interfering RNA (siRNA) was used to study the impact of knockdown of B7-H3 on CD8؉ cell-mediated lysis in skeletal muscle cells.Results. B7-H3 was not detectable on normal muscle fibers. In contrast, its expression was markedly increased on muscle fibers from patients with inflammatory myopathies. Cell-surface staining was most prominent in the contact areas between muscle fibers and inflammatory cells. B7-H3 protein was detected on myoblasts cultured from control and myositis patient muscle tissue as well as in TE671 muscle rhabdomyosarcoma cells. Knockdown of B7-H3 by siRNA in TE671 cells enhanced CD8؉ T cell-specific lysis, indicating a functional role of B7-H3 in the protection of skeletal muscle from immune-mediated lysis.Conclusion. Our results demonstrate that human muscle cells express B7-H3, a functional coinhibitory molecule of the B7 family. B7-H3 may play an important role in muscle-immune interactions, providing further evidence of the active role of muscle cells in local immunoregulatory processes.

Skeletal muscle cells: from local inflammatory response to active immunity

“…Skeletal muscle and immune response M Marino et al inflammatory myopathy lesions; 84 in vitro myoblasts and TE671 rhabdomyosarcoma cells have a constitutive and high expression of B7-H3; silencing of B7-H3 in TE671 enhanced CD8 + T-cell-specific lysis, indicating a functional role of B7-H3 in the protection of skeletal muscle from immune-mediated lysis. 84 The discovery of these new members of the B7 family with strong immuno-inhibitory properties in the muscles demonstrates that muscle cells, through modulation of T-cell functions, can finely balance a proinflammatory stimulus: activation of counteracting mechanisms may represent an attempt to protect muscle fibres from the immune attack in inflammatory conditions (Figure 4a).…”

“…84 The discovery of these new members of the B7 family with strong immuno-inhibitory properties in the muscles demonstrates that muscle cells, through modulation of T-cell functions, can finely balance a proinflammatory stimulus: activation of counteracting mechanisms may represent an attempt to protect muscle fibres from the immune attack in inflammatory conditions (Figure 4a). 85 Modulation of these new B7 family members may therefore become a central strategy to control immune responses after DNA-based gene therapy or vaccination: their correct manipulation can efficiently reduce or enhance local levels of cytokine productions and T-cell activation (Figures 4a and b).…”

Nonimmune mechanisms of muscle damage in myositis: role of the endoplasmic reticulum stress response and autophagy in the disease pathogenesis

“…A recent study shows that leukocyte Ig-like receptor 1 (CD85j) but not CD158 (killer cell Ig-like receptors [KIRs]) is highly expressed in inflammatory cells in muscle, suggesting active interaction between skeletal muscle and immune cells (e.g., dendritic cells) [35]. Also, human skeletal muscle cells not only express common cell surface molecules such as MHC Class I and ICAM-1 but also certain immunoregulatory molecules such as B7 homolog 3 (B7-H3), which may protect from T cell-mediated damage to the skeletal muscle [36]. …”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…It has been demonstrated that perforin‐polarization within endomysial CD8 + T cells occurs toward target myofibers indicative of immunosynapse formation and arguing strongly for a possible recognition of specific antigens presented via MHC class I expressing myofibers 49. In line with this, muscle fibers in IBM patients express co‐stimulatory molecules such as ICOS‐L, CD276, and BB1 on their surface 48, 50, 51…”