Generation of both cortical and Aire⁺ medullary thymic epithelial compartments from CD205⁺ progenitors

Abstract

In the adult thymus, the development of self-tolerant thymocytes requires interactions with thymic epithelial cells (TECs). Although both cortical and medullary TECs (cTECs/mTECs) are known to arise from common bipotent TEC progenitors, the phenotype of these progenitors and the timing of the emergence of these distinct lineages remain unclear. Here, we have investigated the phenotype and developmental properties of bipotent TEC progenitors during cTEC/mTEC lineage development. We show that TEC progenitors can undergo a stepwise acquisition of first cTEC and then mTEC hallmarks, resulting in the emergence of a progenitor population simultaneously expressing the cTEC marker CD205 and the mTEC regulator Receptor Activator of NF-κB (RANK). In vivo analysis reveals the capacity of CD205+ TECs to generate functionally competent cortical and medullary microenvironments containing both cTECs and Aire+ mTECs. Thus, TEC development involves a stage in which bipotent progenitors can co-express hallmarks of the cTEC and mTEC lineages through sequential acquisition, arguing against a simple binary model in which both lineages diverge simultaneously from bipotent lineage negative TEC progenitors. Rather, our data reveal an unexpected overlap in the phenotypic properties of these bipotent TECs with their lineage-restricted counterparts.

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).…”

“…Revealing the mechanisms that underlie the specific expression of these molecules among the different TEC subpopulations would be useful to understand the molecular and cellular mechanisms for the diversification of TEC subpopulations. Along these lines, recent experiments have shown that mTECs are derived from progenitors that express cTEC-associated molecules [14][15][16]. Baik et al showed that the expression of CD205 in a fraction of TECs was detectable in embryonic day 11 (E11) mouse embryos ([14]; commented on in [17]).…”

“…Baik et al showed that the expression of CD205 in a fraction of TECs was detectable in embryonic day 11 (E11) mouse embryos ([14]; commented on in [17]). When they isolated CD205 + CD40 -E15 TECs, placed them in reaggregate thymus organ cultures (RTOCs), and thereafter transplanted them under mouse kidney capsules, they found that CD205 + CD40 -TECs gave rise to CD80 + Aire + mTECs, revealing that embryonic TECs that express the cTEC-associated molecule CD205 contain the potential to differentiate into mTECs [14]. Using transgenic mice that expressed yellow fluorescence protein (YFP) under the control of the IL-7 promoter sequence, in which YFP + cells represented cells that highly expressed IL-7, Ribeiro et al in a paper published in 2013 showed that YFP + TECs isolated from E14.5 mice gave rise to CD80 + mTECs in RTOCs, indicating that embryonic TECs that express high levels of IL-7, and so resemble cTECs, retain the potential to differentiate into mTECs [15].…”

“…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.…”

“…Baik et al showed that the expression of CD205 in a fraction of TECs was detectable in embryonic day 11 (E11) mouse embryos ( [14]; commented on in [17]). When they isolated CD205 + CD40 -E15 TECs, placed them in reaggregate thymus organ cultures (RTOCs), and thereafter transplanted them under mouse kidney capsules, they found that CD205 + CD40 -TECs gave rise to CD80 + Aire + mTECs, revealing that embryonic TECs that express the cTEC-associated molecule CD205 contain the potential to differentiate into mTECs [14].…”