Thymic Microenvironment: Interactions Between Innate Immune Cells and Developing Thymocytes

Abstract

The thymus is a crucial organ for the development of T cells. T cell progenitors first migrate from the bone marrow into the thymus. During the journey to become a mature T cell, progenitors require interactions with many different cell types within the thymic microenvironment, such as stromal cells, which include epithelial, mesenchymal and other non-T-lineage immune cells. There are two crucial decision steps that are required for generating mature T cells: positive and negative selection. Each of these two processes needs to be performed efficiently to produce functional MHC-restricted T cells, while simultaneously restricting the production of auto-reactive T cells. In each step, there are various cell types that are required for the process to be carried out suitably, such as scavengers to clean up apoptotic thymocytes that fail positive or negative selection, and antigen presenting cells to display self-antigens during positive and negative selection. In this review, we will focus on thymic non-T-lineage immune cells, particularly dendritic cells and macrophages, and the role they play in positive and negative selection. We will also examine recent advances in the understanding of their participation in thymus homeostasis and T cell development. This review will provide a perspective on how the thymic microenvironment contributes to thymocyte differentiation and T cell maturation.

Keywords: T cell development; dendritic cell; macrophage; negative selection; positive selection; thymus; thymus repair.

Figure 1

Schematic depiction of T cell development in the thymus. Early thymic progenitors (ETP), arriving from the bone marrow, seed the thymus and receive Notch signals from thymic epithelial cells (TECs) to differentiate into CD4^-CD8^- double negative (DN) T-lineage cells. DN cells that have undergone successful V(D)J rearrangement at TCRβ gene loci differentiate into CD4⁺CD8⁺ double positive (DP) cells. After completing TCRα rearrangements and successfully undergoing positive selection, DPs migrate to the thymus medullary region and are subjected to negative selections while DPs that fail positive selection will be programmed for apoptosis. Cells that successfully passed these checkpoints will exit the thymus as CD4 or CD8 single positive (SP) T cells.

Figure 2

Localization of dendritic cell and macrophage subsets in the thymus. There are 6 subsets of dendritic cells (DCs) and 2 subsets of macrophage (MФ) in the thymus. SIRPα⁺ DCs and pDCs are located closely to the cortical-medullary junction (CMJ), CD8⁺ DCs, activated DCs (aDCs), and CD14⁺SIRPα⁺ moDCs (moDCs) are located within the medullary region, and transendothelial DCs (TE-DCs) are located between the microvessels in the thymus. Timd4⁺ macrophages are located within the cortex and uniquely express Spic and Vcam1, while CX₃CR1⁺ macrophages are located at the CMJ expressing Runx3 and antigen presenting genes, such as H2-Q7.