Thymic Crosstalk Coordinates Medulla Organization and T-Cell Tolerance Induction

Abstract

The thymus ensures the generation of a functional and highly diverse T-cell repertoire. The thymic medulla, which is mainly composed of medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), provides a specialized microenvironment dedicated to the establishment of T-cell tolerance. mTECs play a privileged role in this pivotal process by their unique capacity to express a broad range of peripheral self-antigens that are presented to developing T cells. Reciprocally, developing T cells control mTEC differentiation and organization. These bidirectional interactions are commonly referred to as thymic crosstalk. This review focuses on the relative contributions of mTEC and DC subsets to the deletion of autoreactive T cells and the generation of natural regulatory T cells. We also summarize current knowledge regarding how hematopoietic cells conversely control the composition and complex three-dimensional organization of the thymic medulla.

Keywords: T-cell tolerance; autoimmune regulator; dendritic cells; medulla; medullary thymic epithelial cells; natural regulatory T cells; negative selection; thymic crosstalk.

Figure 1

The thymic medulla is composed of a dense network of distinct subsets of DCs and mTECs. (A) Confocal micrograph of a mouse thymic section stained with antibodies against the DC-specific marker CD11c (blue) and the mTEC-specific marker K14 (red). (B) Three distinct subsets of DCs are located mainly in the medulla: resident cDCs (CD11c^hiCD11b⁻ CD8α^hiSirpα⁻), migratory cDCs (CD11c^hiCD11b⁺CD8α^loSirpα⁺), and pDCs (CD11c^intB220⁺PDCA-1⁺). (C) Schematic representation of mTEC differentiation. mTECs arise from a pool of self-renewing mTEC progenitors. Distinct stages of mTEC maturation can be identified based on the differential expression of MHCII, CD80, and Aire. The end stages of maturation can lead to the emergence of post-Aire mTECs, apoptosis, or to the development of Hassall’s corpuscle.

Figure 2

mTECs and DCs tightly collaborate to delete autoreactive T cells and to induce the generation of nTreg cells. Relevant in vivo studies are indicated in this figure. Tissue-restricted self-antigens (TRAs) expressed and presented by mTECs can lead to the deletion of autoreactive T cells and the induction of nTregs. These self-antigens can also be transferred to and presented by resident cDCs, resulting in T-cell deletion and the induction of nTregs. Furthermore, migratory cDCs and pDCs also reinforce the establishment of central T-cell tolerance via the presentation of antigens captured in the periphery. Migratory cDCs are also involved in T-cell deletion and the induction of nTregs, whereas pDCs only contribute to the deletion of autoreactive T cells in mice. Thymic B cells have also been shown to participate in the deletion of autoreactive T cells and the generation of nTregs.

Figure 3

Key cell types, receptors, and ligands that contribute to Aire⁺ mTEC differentiation and medulla patterning. (A) RANKL, which is expressed by Vγ5⁺ T cells and LTi cells in the embryonic thymus and (B) by CD4⁺ thymocytes and iNKT cells in the post-natal thymus, induces Aire⁺ mTEC differentiation. In the post-natal thymus, crosstalk between mTECs and CD4⁺ thymocytes via CCL19/21–CCR7, LTβR/LTα1β2, and CD80/86–CD28 controls medulla patterning, whereas MHCII/self-antigen–TCR complexes and CD40–CD40L contribute to both the differentiation of Aire⁺ mTECs and patterning of the medulla. Receptors and ligands involved in Aire⁺ mTEC differentiation are represented in green, in medulla patterning in red, and in both processes in yellow. (C) Schematic representation of 3D medullary organization in the post-natal thymus. Aire⁺ mTECs (denoted by a green nucleus) and venules are preferentially localized at the cortico-medullary junction (CMJ).