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 CD8 alpha(+) 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.