Long-term persistence of functional thymic epithelial progenitor cells in vivo under conditions of low FOXN1 expression.

Xin Jin,C Clare Blackburn,Svetlana Ulyanchenko,Craig S Nowell,Frances H Stenhouse

doi:10.1371/journal.pone.0114842

Xin Jin, C Clare Blackburn + Show 3 more

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https://doi.org/10.1371/journal.pone.0114842

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Abstract

Normal thymus function reflects interactions between developing T-cells and several thymic stroma cell types. Within the stroma, key functions reside in the distinct cortical and medullary thymic epithelial cell (TEC) types. It has been demonstrated that, during organogenesis, all TECs can be derived from a common thymic epithelial progenitor cell (TEPC). The properties of this common progenitor are thus of interest. Differentiation of both cTEC and mTEC depends on the epithelial-specific transcription factor FOXN1, although formation of the common TEPC from which the TEC lineage originates does not require FOXN1. Here, we have used a revertible severely hypomorphic allele of Foxn1, Foxn1R, to test the stability of the common TEPC in vivo. By reactivating Foxn1 expression postnatally in Foxn1R /− mice we demonstrate that functional TEPCs can persist in the thymic rudiment until at least 6 months of age, and retain the potential to give rise to both cortical and medullary thymic epithelial cells (cTECs and mTECs). These data demonstrate that the TEPC-state is remarkably stable in vivo under conditions of low Foxn1 expression, suggesting that manipulation of FOXN1 activity may prove a valuable method for long term maintenance of TEPC in vitro.

Highlights

The thymus is the obligate site of T-cell development and is crucial for establishment of the adaptive immune system [1]
We have shown that fetal thymic epithelial progenitor cell (TEPC), when unable to express the pivotal prodifferentiative transcription factor FOXN1, can persist in vivo for at least 6 months while retaining their capacity to differentiate to produce a functional thymus upon release of the block in normal FOXN1 expression
We further show that the thymi built by continuous activation of TEPC resist the decrease in size associated with age-related thymic involution, as evidenced by their sustained size until at least 10 months of age

Summary

Introduction

The thymus is the obligate site of T-cell development and is crucial for establishment of the adaptive immune system [1]. The functional dichotomy between these compartments reflects functional differences between cortical and medullary thymic epithelial cells (cTEC and mTEC respectively). These TEC sublineages have a single origin in the endoderm of the third pharyngeal pouch, and clonal analyses have demonstrated the existence of a common TEPC within the population of cells that founds the TEC lineages [2,3,4]. In Foxn null mice, the thymic primordium forms normally and expresses markers that, within the pharyngeal endoderm, are associated with the thymic epithelial lineage. FOXN1 is not required for thymic epithelial lineage specification [3]. Whether functional TEPC phenotype cells persisted beyond postnatal day 14 was, not tested

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