CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment

Upon recognition of auto-antigens, thymocytes are negatively selected or diverted to a regulatory T cell (Treg) fate. CCR7 is required for negative selection of auto-reactive thymocytes in the thymic medulla. Here, we describe an unanticipated contribution of CCR7 to intrathymic Treg generation. Ccr7−/− mice have increased Treg cellularity because of a hematopoietic but non-T cell autonomous CCR7 function. CCR7 expression by thymic dendritic cells (DCs) promotes survival of mature Sirpα− DCs. Thus, CCR7 deficiency results in apoptosis of Sirpα− DCs, which is counterbalanced by expansion of immature Sirpα+ DCs that efficiently induce Treg generation. CCR7 deficiency results in enhanced intrathymic generation of Tregs at the neonatal stage and in lymphopenic adults, when Treg differentiation is critical for establishing self-tolerance. Together, these results reveal a complex function for CCR7 in thymic tolerance induction, where CCR7 not only promotes negative selection but also governs intrathymic Treg generation via non-thymocyte intrinsic mechanisms. [Display omitted] •CCR7 deficiency results in increased thymic Treg generation and recirculation•Increased Treg generation is due to CCR7 deficiency in thymic dendritic cells•CCR7 promotes survival of thymic Sirpα− MHC class IIhi dendritic cells•CCR7 regulates the composition of thymic DCs to restrain Treg generation CCR7 promotes thymocyte medullary entry and is thus required for negative selection. Hu et al. show that CCR7 also regulates intrathymic generation of regulatory T cells (Tregs) through a non-T cell intrinsic mechanism. CCR7 regulates the composition of the thymic conventional DC compartment, which, in turn, restrains intrathymic Treg generation.