Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus

Abstract

Hassall's corpuscles—first described in the human thymus over 150 years ago¹—are groups of epithelial cells within the thymic medulla. The physical nature of these structures differs between mammalian species². Although Hassall's corpuscles have been proposed to act in both the removal of apoptotic thymocytes^3,4 and the maturation of developing thymocytes⁵ within the thymus, the function of Hassall's corpuscles has remained an enigma. Here we report that human Hassall's corpuscles express thymic stromal lymphopoietin (TSLP). Human TSLP activates thymic CD11c-positive dendritic cells to express high levels of CD80 and CD86. These TSLP-conditioned dendritic cells are then able to induce the proliferation and differentiation of CD4⁺CD8^-CD25^- thymic T cells into CD4⁺CD25⁺FOXP3⁺ (forkhead box P3) regulatory T cells. This induction depends on peptide–major histocompatibility complex class II interactions, and the presence of CD80 and CD86, as well as interleukin 2. Immunohistochemistry studies reveal that CD25⁺CTLA4⁺ (cytotoxic T-lymphocyte-associated protein 4) regulatory T cells associate in the thymic medulla with activated or mature dendritic cells and TSLP-expressing Hassall's corpuscles. These findings suggest that Hassall's corpuscles have a critical role in dendritic-cell-mediated secondary positive selection of medium-to-high affinity self-reactive T cells, leading to the generation of CD4⁺CD25⁺ regulatory T cells within the thymus.