Contrasting models of promiscuous gene expression by thymic epithelium

Abstract

Medullary thymic epithelial cells (mTECs) express a broad spectrum of tissue- restricted self-antigens (TRAs), which are required for the development of central tolerance. A new study suggests that TRA expression is a specialized property of terminally differentiated mTECs. However, as discussed here, an alternative model-whereby TRA expression is regulated by conserved developmental programs active in developing mTECs-may be equally plausible.

Figure 1.

Models of the mechanisms resulting in TRA expression by mTECs. (A) The terminal differentiation model. As a committed mTEC progenitor (p) cell differentiates, it progressively expresses an increasing number of TRAs, starting at an immature (im) stage and culminating in a terminally differentiated (mature [m]) cell that is characterized by high level expression of MHC class II, CD80, Aire, and a broad spectrum of TRAs (represented by colored circles). The role of Aire in this model is undefined but is progressively manifested during mTEC maturation. (B) The developmental model. Progenitors have access to a wide variety of lineage-specific transcriptional programs (and the TRAs regulated by those programs) before differentiation. As part of the differentiation process, some of the transcriptional networks are silenced as individual cells mature. Each of these mature cells might express a peripheral lineage program (i and iii), or might extinguish all peripheral regulators and express an undefined terminal mTEC program (ii). In the developmental model, MHC class II and costimulatory molecules like CD80 would be inducibly expressed on mTECs throughout differentiation in response to cell–cell or other extrinsic signals. We speculate that Aire acts at early stages of mTEC differentiation, perhaps by regulating lineage decisions or by controlling temporal patterns of the differentiation process.