Non-Epithelial Stromal Cells in Thymus Development and Function

Abstract

The thymus supports T-cell development via specialized microenvironments that ensure a diverse, functional and self-tolerant T-cell population. These microenvironments are classically defined as distinct cortex and medulla regions that each contain specialized subsets of stromal cells. Extensive research on thymic epithelial cells (TEC) within the cortex and medulla has defined their essential roles during T-cell development. Significantly, there are additional non-epithelial stromal cells (NES) that exist alongside TEC within thymic microenvironments, including multiple subsets of mesenchymal and endothelial cells. In contrast to our current understanding of TEC biology, the developmental origins, lineage relationships, and functional properties, of NES remain poorly understood. However, experimental evidence suggests these cells are important for thymus function by either directly influencing T-cell development, or by indirectly regulating TEC development and/or function. Here, we focus attention on the contribution of NES to thymic microenvironments, including their phenotypic identification and functional classification, and explore their impact on thymus function.

Keywords: endothelial cell; lymphoid tissue development; mesenchyme cells; thymocyte development; thymus.

Figure 1

Endothelial cells regulate T-cell progenitor entry. Initial steps in thymocyte development involve homing to, and colonizing of, the thymus by bone marrow-derived blood-borne progenitors via blood vessels at the corticomedullary junction (orange dotted line). Entry of these progenitors is controlled by thymic endothelial cells (EC) which regulate this process through a number of different mechanisms detailed in the inset figure (black dotted line/box). ECs express P-selectin, the ligand for which (P-selectin glycoprotein ligand 1, PSGL-1) is expressed by lymphoid progenitor cells. P-selectin-PSGL1 interactions are essential in slowing down progenitor movement, allowing them to interact with ICAM-1 and VCAM-1 expressed by ECs. In adult thymus, CCL25 (ligand for CCR9) which is produced by both TEC and ECs has also been shown to be essential for progenitor homing to the thymus. Additionally, CCR7 is involved in thymus colonization, although its precise ligand requirements (CCL19 and/or CCL21) is not known.

Figure 2

Endothelial cells regulate mature thymocyte egress. Similar to progenitor entry into the thymus, egress of mature thymocytes that have completed their intrathymic development occurs via blood vessels at the corticomedullary junction (orange hashed line). Mature CD4⁺CD8⁻ (SP4) or CD4⁻CD8⁺ (SP8) thymocytes which express the S1P receptor S1P1 migrate from the medulla to the CMJ to begin their exit from the thymus. As detailed in the inset figure (black dotted line/box), mature SP thymocytes first enter the perivascular space (PVS) and then cross the endothelium into the blood via reverse transendothelial migration, with both processes being S1P-dependent. Thymic ECs play an essential role in this process by maintaining the S1P gradient within the thymic parenchyma/PVS. ECs can increase S1P levels through their expression of the S1P transporter Spinster homolog 2 (SPNS2) which transports S1P synthesized through the phosphorylation of sphingosine by sphingosine kinase (SPHK). Conversely, ECs reduce S1P levels through expression of lipid phosphate phosphatase 3 (LPP3) which dephosphorylates S1P to sphingosine or by irreversibly degrading S1P via S1P lyase. These mechanisms maintain the export of mature thymocytes essential to contribute to the peripheral T-cell pool.