Serial progression of cortical and medullary thymic epithelial microenvironments

Abstract

Thymic epithelial cells (TECs) provide key instructive signals for T-cell differentiation. Thymic cortical (cTECs) and medullary (mTECs) epithelial cells constitute two functionally distinct microenvironments for T-cell development, which derive from a common bipotent TEC progenitor. While seminal studies have partially elucidated events downstream of bipotent TECs in relation to the emergence of mTECs and their progenitors, the control and timing of the emergence of the cTEC lineage, particularly in relation to that of mTEC progenitors, has remained elusive. In this review, we describe distinct models that explain cTEC/mTEC lineage divergence from common bipotent progenitors. In particular, we summarize recent studies in mice providing evidence that mTECs, including the auto-immune regulator(+) subset, derive from progenitors initially endowed with phenotypic properties typically associated with the cTEC lineage. These observations support a novel "serial progression" model of TEC development, in which progenitors serially acquire cTEC lineage markers, prior to their commitment to the mTEC differentiation pathway. Gaining a better understanding of the phenotypic properties of early stages in TEC progenitor development should help in determining the mechanisms regulating cTEC/mTEC lineage development, and in strategies aimed at thymus reconstitution involving TEC therapy.

Keywords: Cortex; Medulla; Thymic epithelial cells; Thymus.

Figure 1

Models of thymic epithelial cell development. (A) In the “synchronous” model, uncommitted bipotent TEC progenitors (TEPs) diverge simultaneously to lineage-restricted cortical (cTEPs) and medullary (mTEPs) progenitors, which then progress into mature cTECs and mTECs. (B) In the “serial progression” model, TEPs transverse through a “transitional TEC progenitor” stage (tTEP) that expresses phenotypic and molecular traits associated with cTECs prior to the commitment into a cTEC or mTEC fate. In the asymmetric scenario (top), tTEPs are more closely linked, at the phenotypic and molecular levels, with cTEPs and have the potential to generate both mTEC progenitors and mature cTECs, with the cortical lineage being the “default” pathway. In the symmetric scenario (bottom), tTEPs express both cTEC and as-yet-unidentified mTEC traits prior to lineage specification.