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.

CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells

“…-2875 that CCRL1 + fetal cTECs contain mTEC progenitor activity. These results agree with the recent reports discussed above showing that pTECs progress through a stage in which they express cTECassociated molecules before diversifying into mTECs [11,[14][15][16] (Fig. 1).…”

“…Collectively, the three independent reports [14-16] revealed a new stage in the TEC developmental pathways, i.e. bipotent pTECs progress through a stage in which pTECs display molecular signatures associated with cTECs, before then diversifying into mTECs [11].The new paper by Ribeiro et al [18] in this issue of the European Journal of Immunology initially provides further support regarding this developmental stage of pTECs that express cTEC-associated molecules. To do so, Ribeiro et al [18] analyze the expression of the atypical chemokine receptor CCRL1 during mouse ontogeny.…”

“…For example, cTECs predominantly express keratin 8 (K8), CD205 (DEC205), and CD249 (Ly51), whereas mTECs highly express keratin 5 (K5), CD80, and molecules that bind to the lectin Ulex europaeus agglutinin 1 (UEA1) [9][10][11]. In addition, mTECs, including immature mTECs, strongly express the tight junction molecules claudin-3 and claudin-4 [12].…”

“…The cytokine receptor RANK and the nuclear protein Aire, which are pivotal for mTEC development and function in establishing self-tolerance in T cells, are predominantly detectable in mTECs rather than cTECs [10,11]. Chemokines, which essentially regulate the migration of developing thymocytes, are also unequally expressed between cTECs and mTECs; CCL25 and CXCL12 are more abundant in cTECs than mTECs, whereas CCL19, CCL21, and XCL1 are more highly detectable in mTECs than cTECs [10].…”

“…Development and heterogeneity of cTECs and mTECs. pTECs progress through a stage in which they express cTEC-associated molecules (cpTECs; cTEC-like progenitor TECs), including CCRL1 CD205, β5t, and high levels of IL7, before diversifying into mTECs [11,[14][15][16][17][18]. Signals provided by developing thymocytes regulate the development of CCRL1 high CD205 + β5t + IL7 high cTECs.…”