CCR4 and CCR7 differentially regulate thymocyte subset localization with distinct outcomes for central tolerance

Abstract

AbstractDeveloping thymocytes must efficiently enter the medulla to test if they are autoreactive to diverse self-peptides displayed by thymic antigen presenting cells (APCs). While CCR7 is known to promote medullary entry and negative selection, we previously found that CCR4 contributes to these processes, raising the question of whether CCR4 and CCR7 play redundant roles in central tolerance. Here, synchronized positive selection assays and 2-photon microscopy reveal that CCR4 and CCR7 promote medullary accumulation and negative selection of distinct post-positive selection thymocyte subsets. CCR4 is upregulated within hours of positive selection and promotes medullary entry and clonal deletion of immature post-positive selection thymocytes. In contrast, CCR7 promotes medullary entry and negative selection of mature thymocytes. Our data uncouple CCR7 expression from robust medullary accumulation. Furthermore, CCR4 ligands are expressed by activated thymic APCs, and CCR4 promotes tolerance to self-antigens expressed by these cells. These data support a model in which CCR4 and CCR7 contribute to early and late phases of negative selection, respectively.