Thymic mimetic cells: tolerogenic masqueraders

Abstract

Medullary thymic epithelial cells (mTECs) clonally delete or divert autoreactive T cells by ectopically expressing a diverse array of peripheral-tissue antigens (PTAs) within the thymus. Although thymic stromal cells with histological features of extra-thymic cell types, like myocytes or neurons, have been observed by light microscopy since the mid-1800s, most modern work on PTA expression has focused on the transcription factor Aire. Here, we highlight recent work that has refocused attention on such 'misplaced' thymic cells, referred to collectively as thymic mimetic cells. We review the molecular underpinnings of mimetic cells and their roles in establishing T cell tolerance, and we propose that mimetic cells play important roles in autoimmunity. Finally, we suggest future directions for this emerging area.

Keywords: Aire; T cell tolerance; Thymus; autoimmunity; transcription factor.

Figure 1 (Key Figure):. Model of thymic PTA expression.

(A) Molecular model of PTA induction by Aire (left) and lineage-defining TFs (right). Aire binds promiscuously to mTEC enhancers and promoters and interacts with general transcriptional mechanisms to quasi-randomly activate expression of diverse PTAs [25]. In contrast, lineage-defining TFs bind specifically to cell-type-specific enhancers and drive coordinated expression of biologically coherent sets of PTAs [38]. (B) Cellular model of PTA expression by mTECs. Transit-amplifying TECs give rise to multiple TEC lineages, including cTECs, Ccl21⁺ mTECs, and Aire-stage mTECs [40]. Aire-stage mTECs further differentiate into diverse mimetic cell types characterized by the lineage-defining TFs, chromatin landscapes, and gene expression programs of peripheral cell types [38,39]. Some mimetic cells (i.e., muscle, tuft mTECs) may not necessarily go through an Aire-positive mTEC stage, as indicated by the dashed line [33,38,39]. Note that Ccl21⁺ mTECs have been called “immature” mTECs, but likely represent a separate mTEC lineage as opposed to an “immature” progenitor [40].

Figure 2:. Model of αβ T-cell selection.

Simplified model of αβ T-cell selection. Most thymocytes mature from CD4⁻CD8⁻ double-negative (DN) precursors into CD4⁺CD8⁺ double-positive (DP) thymocytes expressing rearranged αβ TCRs. DP thymocytes undergo positive selection for self-MHC molecule restriction through interactions with cTECs; surviving thymocytes become CD4⁺ and CD8⁺ single-positive (SP) thymocytes and undergo negative selection or agonist selection through interactions with thymic APCs in the cortex (ubiquitous antigens) and medulla (PTAs). mTECs, including diverse mimetic cells, provide PTAs for negative and agonist selection, either directly through presentation on MHC molecules or indirectly through antigen transfer to other thymic APCs, including dendritic cells (DCs).