A unified theory of central tolerance in the thymus

Non-deletional tolerance resulting in the generation of regulatory T cells within the thymus is a key mechanism for the establishment of immunological self-tolerance. How the high-affinity self-reactive regulatory T cells escape negative selection and what type of antigen-presenting cells positively select them within the thymus are unsolved questions. Previous studies suggest that thymic epithelial cells are crucial for the positive selection of regulatory T cells in thymus. A recent study from my group shows that a subset of dendritic cells (that have been "educated" by the thymic stromal lymphopoietin molecule produced by a thymic cell type known as Hassall's corpuscles) positively select regulatory T cells within the medulla of human thymus. Here, I discuss the implications and historical context of this new result and suggest that a subset of mature dendritic cells within the thymic medulla protects the medium- to high-affinity self-reactive T cells from negative deletion and induces their differentiation into regulatory T cells in the thymus.