Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner

Abstract

The postnatal thymus is the primary source of T cells in vertebrates, and many if not all stages of thymocyte development require interactions with thymic epithelial cells (TECs). The Foxn1 gene is a key regulator of TEC differentiation, and is required for multiple aspects of fetal TEC differentiation. Foxn1 is also expressed in the postnatal thymus, but its function after birth is unknown. We generated a Foxn1 allele with normal fetal expression and thymus development, but decreased expression in the postnatal thymus. This down-regulation causes rapid thymic compartment degeneration and reduced T-cell production. TEC subsets that express higher Foxn1 levels are most sensitive to its down-regulation, in particular MHCII hi UEA-1 hi medullary TECs. The requirement for Foxn1 is extremely dosage sensitive, with small changes in Foxn1 levels having large effects on thymus phenotypes. Our results provide the first evidence that Foxn1 is required to maintain the postnatal thymus. Furthermore, the similarities of this phenotype to accelerated aging-related thymic involution support the possibility that changes in Foxn1 expression in TECs during aging contribute to the mechanism of involution. (Blood. 2009;113:567-574) IntroductionThe postnatal thymus consists of a complex cellular and extracellular environment through which developing thymocytes migrate in a stereotypical manner during their differentiation to self-restricted, self-tolerant T cells. 1,2 The principal thymic stromal cell types are thymic epithelial cells (TECs), which are broadly divided into cortical and medullary classes, and have specific functions to promote all stages of thymocyte development. 3,4 The normal postnatal thymus displays dramatic shifts in size and phenotype over the life of the animal due to the influence of external and internal changes. In the early postnatal stage the thymus undergoes rapid logarithmic expansion in size and T-cell production, and the stroma becomes organized and expanded. At about 1 to 2 weeks (in mice), the thymus enters a period of relative homeostasis and high thymic output that continues until early adulthood. This period results in the generation of a normal complement of peripheral T cells with a diverse repertoire. After this point, the thymus gradually undergoes a process known as age-associated involution. The fully involuted thymus has significantly reduced thymopoiesis. The thymic architecture is changed, as TEC numbers decrease and the cortical and medullary compartments break down. 5 Besides a dramatic decrease in the production of naive T cells, the percentage of the most immature (DN1) thymocyte subpopulation is increased in aged mice, 6,7 although the number of early thymic progenitors (ETPs) is decreased. 8,9 Both the initial development and the maintenance of thymic compartment organization and T-cell production require ongoing productive interactions between thymocytes and thymic stromal cells. 10 Failure to maintain the postnatal thymus results in dramatically reduced T-cell production, and thu...

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

“…1M), some of which seem to be thymic nurse cells (25). In complementary studies, we also examined whether βKlotho is expressed in TECs expressing FoxN1, a transcription factor that is critical for thymopoiesis (26). To do this, we used transgenic mice harboring a fluorescent membrane dTomato/membrane EGFP (mT/mG) Cre reporter construct (27) that marks FoxN1 Cre excision by a heritable switch from membrane-targeted tdTomato expression to membrane-targeted EGFP expression.…”

Umbilical cord-derived mesenchymal stem cells regulate thymic epithelial cell development and function in Foxn1−/− mice

“…34 Foxn1 levels, therefore, have significant effects on thymic phenotypes. 35 A reduction in Foxn1 expression has been shown to cause thymic compartment degeneration, a loss of specific TEC subsets and reduced T-cell production. 35 The deletion of Foxn1 inhibited the development of mature TECs and reduced the number of total thymocytes, which is observed during normal thymic aging.…”

“…35 A reduction in Foxn1 expression has been shown to cause thymic compartment degeneration, a loss of specific TEC subsets and reduced T-cell production. 35 The deletion of Foxn1 inhibited the development of mature TECs and reduced the number of total thymocytes, which is observed during normal thymic aging. 5 In our study, we chose the Foxn1 2/2 mouse as a model to investigate the biological function of MSCs in T-cell regulation.…”

FOXN1 recombinant protein enhances T‐cell regeneration after hematopoietic stem cell transplantation in mice

“…FOXN1 is expressed in fetal thymus and postnatal TECs and its expression is progressively down-regulated with aging [15,16,[22][23][24][25]. FOXN1 is required not only for TEC development in fetal thymus, but also for maintenance of the postnatal thymus [15,16,23,24,26]. The reduced expression or induced deletion of FOXN1 resulted in reduced TEC number and a disrupted thymic microenvironment [16,18,22,24,27].…”

“…These results suggest that FOXN1 induced mTEC proliferation is due, at least in part, to the enhanced expression of cyclin D1. Whether cyclin D1 and p53 are the directly or indirectly downstream target genes remains to be determined.In addition to an increased number of mature TECs, rFOXN1 treatment also increased the number of MHC II lo immature TECs.Several investigators have also shown that, in addition to maintain existing TECs, FOXN1 also regulates TEC progenitors [15,16,18,27,31], which may also contribute to the increased number of TECs. The number of ETPs was also significantly increased after rFOXN1 treatment.…”