Journal
ARTHRITIS AND RHEUMATISM
Volume 64, Issue 10, Pages 3441-3451Publisher
WILEY
DOI: 10.1002/art.34551
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Funding
- Association Francaise contre les Myopathies [NMNM2-2010 N 14194/14499/15155]
- Agence Nationale pour la Recherche [MYO-REPAIR ANR-07BLAN-0060]
- Region Ile de France
- National Natural Science Foundation of China [81171724]
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Objective To investigate the influence of myoinjury on antigen presentation to T cells in draining lymph nodes (LNs). Methods Muscle crush was performed in mice injected with exogenous ovalbumin (OVA) and in transgenic SM-OVA mice expressing OVA as a muscle-specific self antigen. Antigen exposure and the resulting stimulation of T cell proliferation in draining LNs was assessed by transferring carboxyfluorescein succinimidyl ester (CFSE)labeled OVA-specific CD8+ and CD4+ T cells from OT-I and OT-II mice and by measuring the dilution of CFSE, which directly reflects their proliferation. The role of monocyte-derived dendritic cells (DCs) in T cell priming was assessed using pharmacologic blockade of DC migration. Immunofluorescence was used to detect CD8+ T cells, inflammatory monocyte-derived DCs, and type I major histocompatibility complex (MHC)expressing myofibers in crushed muscle, and to assess expression of perforin, interferon-? (IFN?), interleukin-2 (IL-2), IL-10, and transforming growth factor beta 1 (TGF beta 1). Results OVA injection into intact muscle induced strong proliferation of CD4+ and CD8+ T cells, indicating efficient exposure of soluble antigens in draining LNs. OVA-specific CD8+ T cell proliferation in draining LNs of SM-OVA mice required myoinjury and was unaffected by pharmacologic inhibition of monocyte-derived DC migration. On day 7 postinjury, activated CD8+ T cells expressing perforin, IFN? and IL-2 were transiently detected in crushed muscle, and these cells were in close contact with class I MHCpositive regenerating myofibers. Beginning on day 7, the immunosuppressive cytokines IL-10 and TGF beta 1 were conspicuously expressed by CD11b+ cells, and CD8+ T cells rapidly disappeared from the healing muscle. Conclusion Myofiber damage induces an episode of muscle antigenspecific CD8+ T cell proliferation in draining LNs. Activated CD8+ T cells transiently infiltrate the injured muscle, with prompt control by immunosuppressive cues. Inadequate control might favor sustained autoimmune myositis.
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