Résumé :
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Regulatory CD4+CD25+ T cells prevent the activation of auto-reactive T cells and play a key role in the induction of peripheral tolerance. We recently showed that regulatory T (Treg) cells are severely defective in the thymus from patients with Myasthenia Gravis (MG). A similar analysis using peripheral blood cells revealed also a defective suppressive function in MG patients, although at a lesser extent. The phenotype of MG thymic Treg cells appear different from control ones, according to Fas and CXCR3 expression, while no difference was observed in the periphery. These results raise the possibility that intrathymic events could mediate the regulatory function and be at the origin of Treg cell defects in MG patients.Stromal thymic epithelial cells (TEC) are known to contribute to the differentiation of Treg cells and we previously showed that TEC from MG thymus overproduce inflammatory cytokines such as IL-1 and IL-6. We wondered whether TEC from MG patients differ from non-MG TEC in their ability to modulate Treg cell activity. To this end, TEC from MG and non-MG thymus were co-cultured with normal total CD4+, Treg or Teff cells to evaluate the influence of TEC on markers associated with Treg function (CD25 and FoxP3). We found that TEC from control thymus enhance the expression of CD25 and FoxP3 and protect Treg function. These effects were TEC-specific since they were not observed when using thymic myoid cells or epithelial colorectal cells. We also showed that direct contact was not required for the maintenance of the Treg phenotype, suggesting that the effects were mediated through soluble factors. MG TEC also led to maintenance of the Treg phenotype in CD4+ cells but the suppressive activity of CD4+CD25+ cells issued from co-culture with MG TEC was significantly impaired. In the same time, MG defective CD4+CD25+ cells recovered partially their suppressive function when cultured with control TEC, suggesting that the suppressive defect of MG Treg cells is not intrinsic and can be repaired.Altogether, these results demonstrate for the first time a direct role of TEC in mediating Treg phenotype and function. These data also suggest that MG TEC are implicated into the defective function of Treg cells and into the chronic thymic inflammatory environment affecting MG patients. The identification of the soluble factors involved in these effects is in progress.
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