CCR7 modulates the generation of thymic regulatory T cells by altering the composition of the thymic dendritic cell compartment

Abstract

Abstract Upon recognition of auto-antigens, thymocytes are negatively selected or diverted to a regulatory T cell (Treg) fate. Both dendritic cells (DC) and medullary thymic epithelial cells (mTEC) present antigens to tolerize thymocytes. CCR7 guides thymocytes into the medulla, promoting encounters with medullary DC and mTEC. Thus, in the absence of CCR7 negative selection of auto-reactive thymocytes is impaired and autoimmunity ensues. Here we describe an unanticipated, non-thymocyte intrinsic contribution of CCR7 to intrathymic Treg generation. We find that Ccr7−/− mice have increased Treg cellularity, due to a hematopoietic, but non-T cell autonomous function of CCR7. In addition to thymocytes, thymic DC also express CCR7, which promotes survival of Sirpα−DC. Without CCR7, Sirpα−DC are preferentially lost, altering the composition of the conventional thymic DC compartment to favor intrathymic Treg generation. CCR7 deficiency results in enhanced production of thymic Treg at the neonatal stage and in lymphodeficient adults, when Treg generation is most critical for the establishment of self-tolerance. Together these results reveal a more complex function for CCR7 in thymic tolerance induction, in which CCR7 not only promotes negative selection through its effect on thymocyte localization, but also governs intrathymic Treg generation via non-thymocyte intrinsic mechanisms.