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

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 64; no. 10; pp. 3441 - 3451
• Main Authors: Liao, Hua, Franck, Emilie, Fréret, Manuel, Adriouch, Sahil, Baba-Amer, Yasmine, Authier, Francois-Jerome, Boyer, Olivier, Gherardi, Romain K.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-10-2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Adoptive Transfer; Animals; Antigen Presentation - immunology; Biological and medical sciences; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell growth; Cell Movement - immunology; Cell Proliferation; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Diseases of the osteoarticular system; Immune system; Lymph Nodes - cytology; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphocyte Activation - immunology; Lymphocytes; Medical research; Medical sciences; Mice; Mice, Transgenic; Muscle, Skeletal - cytology; Muscle, Skeletal - immunology; Muscle, Skeletal - injuries; Muscle, Skeletal - metabolism; Antigen; Vertebrata; Mammalia; Lymph node; Mouse; Immunological investigation; Animal; Rodentia; T-Lymphocyte; Rheumatology; Models
• ISSN: 0004-3591; 2326-5191; 1529-0131; 2326-5205
• DOI: 10.1002/art.34551

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.