Résumé :
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The mechanisms of immunological tolerance to skeletal muscle autoantigens remains mostly unknown. To investigate this issue, we generated transgenic mice expressing the neo-autoantigen ovalbumin (OVA) exclusively in skeletal muscle (SM-OVA mice). SM-OVA mice were bred with OT-I or OT-II mice that possess a transgenic T cell receptor specific for OVA peptides presented by MHC class I or II, respectively. Hence, in this model, T lymphocytes are massively biased toward the recognition of OVA that is abundantly represented in muscle fibers. Both [SM-OVA x OT-I]F1 and [SM-OVA x OT-II]F1 appeared tolerant to OVA and no sign of muscle autoimmunity was detected. Tolerance to OVA did not involve clonal deletion nor anergy of T cells. We neither evidenced an increased regulatory T cell compartment. Rather, CD4+ T cell tolerance resulted from a mechanism of ignorance revealed by their response following OVA immunization. In marked contrast, CD8+ T cells exhibited a loss of their capacity to mount an OVA-specific cytotoxic response. This phenomenon was associated with up-regulation of the immunoregulatory programmed cell death-1 (PD-1) molecule. Adoptive transfer experiments further showed that OVA expression in skeletal muscle was required to maintain this functional tolerance. These results establish, for the first time, an asymmetric model of immunological tolerance to muscle autoantigens involving antigen ignorance for CD4+ T cells, whereas muscle autoantigens recognized by CD8+ T cells results in blockade of their cytotoxic function. These observations may be helpful for understanding the breakage of tolerance in autoimmune muscle diseases.
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