The cellularity of thymic regulatory T cells is regulated by CCR7 through a non-cell intrinsic mechanism (HEM7P.228)

Abstract

Abstract To ensure central tolerance, developing T cells must enter the thymic medulla to encounter self-antigens that induce autoreactive cells to undergo apoptosis or differentiation into the regulatory T cell (Treg) lineage. Both dendritic cells (DCs) and medullary thymic epithelial cells (mTECs) present antigens to tolerize thymocytes. mTECs express a diverse array of self-antigens, while DCs express auto-antigens acquired both in the periphery and from mTECs. Thymocytes must interact efficiently with these medullary antigen presenting cells (APCs) to encounter the full spectrum of self- antigens. CCR7 guides thymocytes into the medulla, promoting encounters with medullary DCs and mTECs. In the absence of CCR7, negative selection of autoreactive thymocytes is impaired, and autoimmunity ensues. Surprisingly, thymic Treg cellularity is increased in Ccr7-/- mice. Diminished negative selection has previously been associated with a concomitant increase in Treg differentiation. Thus, we anticipated that a cell-intrinsic defect in CCR7-/- thymocytes would account for increased Treg generation. Instead, a series of bone marrow chimeras demonstrate that CCR7-deficient non-T, non-B lineage hematopoietic cells account for increased Treg cellularity. Expression profiling revealed expression of Ccr7 by thymic DCs. We present evidence that CCR7 deficiency in thymic DCs is responsible for increased Treg cellularity, suggesting that CCR7 has pleiotropic effects on thymic central tolerance.