CCR4 is required for efficient thymocyte medullary entry and central tolerance induction (HEM7P.230)

Abstract

Clonal deletion of auto-reactive thymocytes is essential for the establishment of central tolerance. The thymic medulla is a specialized microenvironment in which post-positive selection thymocytes are screened for reactivity against a wide range of self-antigens. Autoreactive cells are tolerized via clonal deletion or differentiation into the regulatory T cell lineage. Both thymic dendritic cells (DCs) and medullary thymic epithelial cells (mTECs) present auto-antigens to thymocytes to induce central tolerance. Thus, it is critical that post-positive selection thymocytes enter the medulla and interact efficiently with antigen-presenting cells therein to avoid export of autoreactive naïve T cells. We previously demonstrated that although CCR7 is required for medullary accumulation of thymocytes, additional GPCRs must be involved in medullary entry. Here we report that CCR4 is expressed by post-positive selection thymocytes, while CCR4 ligands are expressed by thymic DCs. Using two-photon time-lapse microscopy, we find that CCR4 is required for accumulation of post-positive selection thymocytes in the medulla, as well as efficient interactions between thymocytes and medullary DCs. In the absence of CCR4, thymocytes fail to undergo clonal deletion to low avidity antigens, autoreactive naïve T cells accumulate in secondary lymphoid organs, and autoimmunity ensues. Taken together, these data demonstrate an essential role for CCR4 in the establishment of thymic central tolerance.