Abstract
Following positive selection, thymocytes migrate into the medulla where they encounter diverse self-antigens that induce central tolerance. Thymocytes expressing T cell receptors (TCRs) with high affinity for self-antigens displayed by medullary antigen presenting cells (APCs) undergo either negative selection or diversion to the regulatory T cell (Treg) lineage, thus ensuring maturation of non-autoreactive T cells. Because many self-antigens are expressed by only a small percentage of medullary thymic epithelial cells, thymocytes must enter the medulla and efficiently scan APCs therein to encounter the full array of self-antigens that induce central tolerance. Chemokine receptors play a critical role in promoting medullary entry and rapid motility of post-positive selection thymocytes. We found that the chemokine receptor CCR8 is expressed by post-positive selection CD4+ single positive (SP) thymocytes in mice, while the corresponding chemokine ligands are expressed by medullary APCs, and thus hypothesized that CCR8 would promote thymocyte medullary entry and/or rapid motility to induce negative selection. However, despite a subtle decline in thymocyte medullary accumulation and the presence of autoantibodies in aged CCR8-deficient mice, CCR8 was not required for thymocyte differentiation, rapid motility, or negative selection.
Highlights
Central tolerance in the thymus ensures that T cells that complete thymocyte maturation and selection are largely self-tolerant [1,2]
Analysis of our previous gene expression profiling data from thymocyte and thymic stromal cell subsets revealed that CCR8 was highly expressed by early post-positive selection CD4+ SP (CD4SP) cells, and to some extent by CD8+ SP (CD8SP) cells, while the ligand CCL1 was expressed by MHCIIhiCD80hi Medullary thymic epithelial cells (mTECs) cells, and the ligand CCL8 was expressed by both mTECs and dendritic cells (DCs) [19]. qRT-PCR analysis of FACS sorted thymocyte subsets (Figure A in S1 Fig) confirmed that post-positive selection CD4+ CD69+ thymocytes upregulated CCR8 expression, which was diminished in the mature CD4+ CD69- cells; CD8SP cells expressed minimal levels of CCR8 (Fig 1A)
Because the numerous self-antigens presented in the medulla are expressed at low levels by rare medullary antigen presenting cells (APCs) [9,10,11], it is critical that post-positive selection thymocytes efficiently enter the medulla and migrate rapidly therein to encounter the full array of self-antigens that promote central tolerance prior to egress to the periphery
Summary
Central tolerance in the thymus ensures that T cells that complete thymocyte maturation and selection are largely self-tolerant [1,2]. The thymus, which is divided into two main regions, the outer cortex and the central medulla, provides a specialized environment in which thymic stromal cells interact with thymocytes to induce their differentiation and selection [1,3]. As thymocytes mature, they must interact sequentially with cortical and medullary stromal cells. Migration of thymocytes between the cortex and medulla is orchestrated by chemokine receptors, a subset of G-protein coupled receptors (GPCR) that are differentially expressed by distinct thymocyte maturation stages [4,5].
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