E-protein–regulated expression of CXCR4 adheres preselection thymocytes to the thymic cortex

Abstract

Preselection thymocytes are normally retained in the thymic cortex, but the mechanisms responsible remain incompletely understood. We now report that deletion of genes encoding the E-protein transcription factors E2A and HEB disorders chemokine receptor expression on developing thymocytes to allow escape of preselection TCR−CD8+ thymocytes into the periphery. We document that CXCR4 expression normally anchors preselection thymocytes to the thymic cortex via interaction with its ligand CXCL12 on cortical thymic epithelial cells, and that disruption of CXCR4–CXCL12 engagements release preselection thymocytes from the thymic cortex. We further document that CXCR4 expression must be extinguished by TCR-mediated positive selection signals to allow migration of TCR-signaled thymocytes out of the thymic cortex into the medulla. Thus, E-protein transcription factors regulate the ordered expression pattern of chemokine receptors on developing thymocytes, and the interaction of the chemokine receptor CXCR4 with its ligand adheres TCR-unsignaled preselection thymocytes to the thymic cortex.

Heparan sulfate is essential for thymus growth

“…HS interacts with >300 extracellular molecules ( 30 ), and singling out any one of them as responsible for the phenotype is nearly impossible. We decided to take a candidate approached and started by testing the importance of the interaction of HS with the chemokines CCL19, CCL21, and CXCL12 that have well-characterized roles in directing thymocytes to different microenvironments ( 9 , 13 , 14 ). Binding of these chemokines to HS on thymic fibroblasts could establish localized fields and haptotactic gradients that could be important for the motility of various cells in the organ and their successful development.…”

“…DP thymocytes are the most abundant cell population in the thymus, and they occupy the majority of the cortex. They are thought to be retained there by the action of CXCL12 ( 12 , 13 ). Cells that successfully rearrange the TCRα chain and pass positive selection then migrate to the medulla under the influence of CCR7 ligands, CCL19 and CCL21 ( 14 ), and perhaps CCR4 ligands, CCL17 and CCL22 ( 15 ).…”

Generation and Regeneration of Thymic Epithelial Cells

“…For example, CXCR4-CXCL12 interactions regulate the intrathymic positioning of T cell progenitors (14) while the maturation of pre-TCR expressing CD4 − CD8 − progenitors requires CXCR4-CXCL12 to act in concert with Notch signaling in order to drive β-selection (15,16). For later stages of thymocyte development, CXCL12 has recently been reported to act as a cortex retention factor for CD4 + CD8 + thymocytes, which may enable cells to stay within the thymic cortex in order to undergo correct maturational events, including positive selection (17). Interestingly, of relevance to these studies that indicate the importance of CXCL12-CXCR4, is analysis of the expression and distribution pattern of CXCL12.…”

The Timing and Abundance of IL-2Rβ (CD122) Expression Control Thymic iNKT Cell Generation and NKT1 Subset Differentiation

“…To understand the role of IL-2Rb in thymic iNKT cell generation, we first examined IL-2Rb expression on iNKT cells in the context of ab T cell development in the thymus. The process of thymocyte positive selection and maturation can be visualized using the combination of the two surface markers CD69 and CCR7 which identifies 5 distinct developmental stages, progressing from stage I to stage V (Figure 1A, top) (27). TCR engagement of immature thymocytes (stage I) induces the expression CD69 (stage II) followed by the upregulation of the chemokine receptor CCR7, so that CD69 + CCR7 int cells (stage III) correspond to thymocytes undergoing positive selection and lineage commitment.…”