Autophagy in the Thymic Epithelium Is Dispensable for the Development of Self-Tolerance in a Novel Mouse ModelReportar como inadecuado

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The thymic epithelium plays critical roles in the positive and negative selection of T cells. Recently, it was proposed that autophagy in thymic epithelial cells is essential for the induction of T cell tolerance to self antigens and thus for the prevention of autoimmune diseases. Here we have tested this hypothesis using mouse models in which autophagy was blocked specifically in epithelial cells expressing keratin 14 K14, including the precursor of thymic epithelial cells. While the thymic epithelial cells of mice carrying the floxed Atg7 gene ATG7 f-f showed a high level of autophagy, as determined by LC3 Western blot analysis and fluorescence detection of the recombinant green fluorescent protein GFP-LC3 reporter protein on autophagosomes, autophagy in the thymic epithelium was efficiently suppressed by deletion of the Atg7 gene using the Cre-loxP system ATG7 f-f K14-Cre. Suppression of autophagy led to the massive accumulation of p62-sequestosome 1 SQSTM1 in thymic epithelial cells. However, the structure of the thymic epithelium as well as the organization and the size of the thymus were not altered in mutant mice. The ratio of CD4 to CD8-positive T cells, as well as the frequency of activated CD69+ CD4 T cells in lymphoid organs, did not differ between mice with autophagy-competent and autophagy-deficient thymic epithelium. Inflammatory infiltrating cells, potentially indicative of autoimmune reactions, were present in the liver, lung, and colon of a similar fraction of ATG7 f-f and ATG7 f-f K14-Cre mice. In contrast to previously reported mice, that had received an autophagy-deficient thymus transplant, ATG7 f-f K14-Cre mice did not suffer from autoimmunity-induced weight loss. In summary, the results of this study suggest that autophagy in the thymic epithelium is dispensable for negative selection of autoreactive T cells.

Autor: Supawadee Sukseree, Michael Mildner, Heidemarie Rossiter, Johannes Pammer, Cheng-Feng Zhang, Ramida Watanapokasin, Erwin Tschachl



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