Myoinjury transiently activates muscle antigen-specific CD8+ T cells in lymph nodes in a mouse model.

Hua Liao (1, 2) , Emilie Franck (3) , Manuel Fréret (3) , Sahil Adriouch (2) , Yasmine Baba-Amer (1) , François-Jérôme Authier (4) , Olivier Boyer (3) , Romain K. Gherardi (1)

1 IMRB - Institut Mondor de Recherche Biomédicale
2 Department of Anatomy
3 Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes
4 U955 Inserm - UPEC - IMRB - "Biologie du système neuromusculaire" [Créteil]

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-γ (IFNγ), interleukin-2 (IL-2), IL-10, and transforming growth factor β1 (TGFβ1). 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, IFNγ and IL-2 were transiently detected in crushed muscle, and these cells were in close contact with class I MHC-positive regenerating myofibers. Beginning on day 7, the immunosuppressive cytokines IL-10 and TGFβ1 were conspicuously expressed by CD11b+ cells, and CD8+ T cells rapidly disappeared from the healing muscle. CONCLUSION: Myofiber damage induces an episode of muscle antigen-specific 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.

Domaines: Biochimie, Biologie Moléculaire

Hua Liao, Emilie Franck, Manuel Fréret, Sahil Adriouch, Yasmine Baba-Amer, et al.. Myoinjury transiently activates muscle antigen-specific CD8+ T cells in lymph nodes in a mouse model.: Myoinjury and CD8+ T-cell activation. Arthritis and Rheumatism, 2012, 64 (10), pp.3441-51. ⟨10.1002/art.34551⟩. ⟨inserm-00750113⟩