Formation of a functional thymus initiated by a postnatal epithelial progenitor cell

Abstract

The thymus is essential for the generation of self-tolerant effector and regulatory T cells. Intrathymic T-cell development requires an intact stromal microenvironment, of which thymic epithelial cells (TECs) constitute a major part. For instance, cell-autonomous genetic defects of forkhead box N1 (Foxn1) and autoimmune regulator (Aire) in thymic epithelial cells cause primary immunodeficiency and autoimmunity, respectively. During development, the thymic epithelial rudiment gives rise to two major compartments, the cortex and medulla. Cortical TECs positively select T cells, whereas medullary TECs are involved in negative selection of potentially autoreactive T cells. It has long been unclear whether these two morphologically and functionally distinct types of epithelial cells arise from a common bi-potent progenitor cell and whether such progenitors are still present in the postnatal period. Here, using in vivo cell lineage analysis in mice, we demonstrate the presence of a common progenitor of cortical and medullary TECs after birth. To probe the function of postnatal progenitors, a conditional mutant allele of Foxn1 was reverted to wild-type function in single epithelial cells in vivo. This led to the formation of small thymic lobules containing both cortical and medullary areas that supported normal thymopoiesis. Thus, single epithelial progenitor cells can give rise to a complete and functional thymic microenvironment, suggesting that cell-based therapies could be developed for thymus disorders.

FGFR2IIIb signaling regulates thymic epithelial differentiation

“…Progenitor thymic epithelial cells physically demonstrated in the fetal thymus (Rossi et al, 2006), also persist in the postnatal thymus (Bleul et al, 2006); however, the phenotypic characteristics of these postnatal progenitor cells has yet been determined. The growing appreciation that postnatal thymic epithelium is mitotically active (Gillard and Farr, 2006;Yang et al, 2006;Rossi et al, 2007b) lends additional support to the proposition that the representation of different epithelial compartments in the postnatal thymus is the result of a dynamic equilibrium between a progenitor population and its differentiating progeny.…”

“…In the postnatal thymus, subsets of TE cells that simultaneously express both cortical and medullary markers have been proposed to be the immediate precursors to the cortical and medullary TE populations (Ropke et al, 1995;Klug et al, 1998) and progenitor epithelial cells within the postnatal thymus capable of giving rise to a complete thymic environment have been demonstrated functionally (Bleul et al, 2006).…”

Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation

“…The presence of a progenitor MTEC population in the adult thymus has been inferred by demonstrations of cells with progenitor activity in the fetal thymus (14 -16) and recently demonstrated in adult thymus (17), although the full developmental potential of these cells has not been determined. We have previously established that the Nanog, Oct4, and Sox2 core transcriptional factors of multipotentiality (18,19), are expressed within the MTEC population and have proposed this to reflect the presence of a developmentally flexible progenitor epithelial population in the adult thymus (8).…”

L’épithélium thymique, un passé dans la dualité et un présent unifié

“…La question est donc maintenant de comprendre quels mécanismes survenus au cours de l'évolution sont responsables de la perte, par le thymus, de la capacité de promouvoir le développement des cellules B (Tableau I). L'ensemble de ces données devraient permettre d'envisager sous un angle teur foetal décrit par Gill [8]. Pourtant, la caractérisation et la purification de ces progéniteurs épithéliaux thymiques bipotents ont jusqu'ici rencontré un succès limité et leur phénotype complet reste encore à définir.…”