Résumé :
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Myoinjury elicits an innate immune response with local generation of monocyte-derived "inflammatory" dendritic cells (Brigitte et al, Arthritis Rheum 2010). The adaptative immune response takes place in draining lymph nodes (dLNs) and spleen where naive T cells become primed by specialized antigen presenting cells (APCs), mainly dendritic cells (DCs). To investigate influence of myoinjury on T-cell priming in vivo, we first compared 2 mouse models of tibialis anterior myoinjury (Notexin injection vs crush). TCR transgenic OVA-specific CD8+ and CD4+ T cells were isolated from spleen of OT-I and -II mice, respectively, and labelled with the intracellular dye CFSE. These cells were adoptively transferred by the i.v. route at d1 after myoinjury. Soluble OVA was injected in the injured muscle at d2. Priming of CD4+ and CD8+ T cells from dLNs (d4 and d7) was assessed by proliferation-dependent fluorescence loss visualized by flow cytometry.In the absence of myoinjury, OVA injection induced both CD4+ and CD8+ T-cell priming at both d4 and d7. Notexin inhibited both CD8+ (d4) and CD4+ (d4 and d7) T-cell priming, suggesting a direct toxic effect on immune cells. This was further confirmed by dose-dependent Notexin cytotoxicity on T lymphocytes in vitro. In contrast, mechanic crush injury increased the number of proliferating CD8+, but not CD4+, T-cells at d7 as compared to the intact mouse.Then we used transgenic SM-OVA mice that selectively express OVA as a self antigen in skeletal muscle (Calbo et al, J Immunol 2008). At d7 after single crush without exogenous OVA, increased the frequency of proliferating CD8+, but not CD4+, T-cells compared to intact SM-OVA mice. Addition of exogenous OVA, increased the CD8+ T-cell priming as compared to uninjured SM-OVA control mice.Interestingly, 7 days after crush injury in WT mice, CD8+ cells were conspicuously detected in the endomysium, in close contact to myofibers.In conclusion, notexin inhibits T-cell response by an unexpected toxic effect on immune cells whereas mechanic myoinjury modulates adaptative immune response to both exo-antigens and muscle-specific auto-antigens by increasing priming of CD8+, but not CD4+, T-cells. The role of myofiber damage in triggering initial autoimmune response in polymyositis deserves further investigation.
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