Chapter 16 - Roles of Autophagy in the Thymic Epithelium

Abstract

Epithelial cells have central roles in the development of the thymus and in the selection of T cells in the thymus. Several recent reports have demonstrated active autophagy in thymic epithelial cells. The lipidated form of the autophagy-associated protein LC3 is present in the thymus, and autophagic vesicles are abundant in thymic epithelium. Recombinant fusion of green fluorescent protein to LC3 in a transgenic mouse model has confirmed the high proportion of autophagy-positive thymic epithelial cells. Suppression of autophagy by targeted gene deletion and grafting of thymi from autophagy-deficient embryos into athymic mice led to the development of severe autoimmunity in multiple organs, indicating a failure of autophagy-deficient thymic epithelium to appropriately support the negative selection of autoreactive T cells. Depending on expression levels and intracellular localization of antigens, autophagy appears to be essential for the loading of some but not all self-peptides onto MHC class II molecules within medullary thymic epithelial cells. In spite of these data arguing for a critical direct role of epithelial cells in antigen presentation within the thymus, signs of autoimmune disease do not develop in mouse models that lack either one of the autophagy-related genes Atg5 or Atg7 in the endogenous thymic epithelium. Thus, autophagy is highly active in normal thymic epithelium and involved in distinct aspects of T cell selection; however, its suppression does not lead to severe autoimmunity.