Epithelial and dendritic cells in the thymic medulla promote CD4(+)Foxp3(+) regulatory T cell development via the CD27–CD70 pathway

CD4(+)Foxp3(+) regulatory T cells (T(reg) cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27–CD70 co-stimulation in the thymus rescues developing T(reg) cells from apoptosis and thereby promotes T(reg) cell generation. Genetic ablation of CD27 or its ligand CD70 reduced T(reg) cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4(+)Foxp3(−) T cell numbers. The CD27–CD70 pathway was not required for pre-T(reg) cell generation, Foxp3 induction, or mature T(reg) cell function. Rather, CD27 signaling enhanced positive selection of T(reg) cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic T(reg) cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire(−) and Aire(+) medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to T(reg) cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α(+) subset of thymic DCs promoted T(reg) cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27–CD70 co-stimulation rescues developing T(reg) cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.