Foxn1 is a key regulator of TEC differentiation and proliferation throughout the thymus lifespan

Read Also

Perhaps the best-known mouse mutants affecting thymic epithelial cells carry mutations at the nude locus, which encodes Foxn1 (99-101). Foxn1 is a forkhead transcription factor required for all TEC differentiation (81, 98). The requirement for Foxn1 for multiple stages of fetal TEC differentiation has been summarized many times, including in a recent review (102). Here, we will focus on the most recent studies regarding the role of Foxn1 in the postnatal thymus.

The early studies of Foxn1 gene expression showed widespread expression in postnatal cTEC and mTEC (101). In contrast, an analysis of Foxn1 protein distribution concluded that Foxn1 protein was not detected in most TECs in the postnatal thymus, and that its presence did not correlate with the expression of the known functional markers Dll4 and CCL25. Based on these data, this study predicted that Foxn1 did not play a significant role in postnatal thymus function, and further suggested that Foxn1-negative TECs may play an important role in postnatal thymus function (103). More recent studies from the Manley lab (104) and others (103) (Nowell and Blackburn, unpublished) have shown that Foxn1 expression is dynamically modulated in different TEC populations, and suggests that that this quantitative requirement for specific levels of Foxn1 may be essential for specific TEC subpopulations to develop or be maintained (104)( Nowell and Blackburn, unpublished). Furthermore, analysis of Foxn1 gene expression using a lacZ allele suggested that most TEC retain Foxn1 gene expression through 12 months of age (104), suggesting that the method of detecting Foxn1 expression may be critical to identifying TECs expressing lower Foxn1 levels. A recent report used a diptheria toxin-based approach to eliminate Foxn1-positive TECs during fetal or postnatal development to conclude that all functional TECs develop from Foxn1-positive cells, and that only Foxn1-lineage TEC can function to support thymocyte development (98). These studies are not completely definitive with respect to the expression of Foxn1 in TESC/TEPC, as mentioned above (section 4.3), but do strongly support a substantial and ongoing requirement for Foxn1 in the postnatal thymus. Other studies using an allele of Foxn1 expressing Cre recombinase to activate marker genes or delete other genes in TECs also clearly show that Foxn1 is expressed in the vast majority, if not all, TECs in both the fetal and adult thymus at some point in their development (16, 105, 106), even if they reside in cysts or have subsequently down regulated Foxn1 expression (98, 107). Partial deletion of the Foxn1 gene using a conditional allele also supported a requirement for Foxn1 in the postnatal thymus (108, 109). Thus, the balance of data clearly supports a model in which Foxn1 is expressed in most TECs at some level throughout life, and that Foxn1 remains a critical regulator of both the fetal and postnatal thymus.

Genetic data also show that proper modulation of Foxn1 levels is required to generate and maintain the correct composition, structure, and function of the postnatal thymus. Reduced Foxn1 expression has been identified as an early event in thymic involution (110). The consequences of this level of down regulation were identified by analysis of an allele of Foxn1 in which premature postnatal down regulation of Foxn1 expression to ~30% of young adult levels occurs (104). This reduced level of Foxn1 induces a premature involution phenotype associated with specific changes in the proliferation and differentiation of specific TEC subsets. These data also suggest that specific TEC subsets require different levels of Foxn1 for their development and/or maintenance, and that modulating Foxn1 levels functions to balance or coordinate TEC differentiation and proliferation during formation and maintenance of the thymic microenvironment. Reduced Foxn1 expression with age is likely to be a major factor contributing to disintegration of the TEC network and inability to support T cell development during involution, and is therefore a strong candidate for a target for inducing thymic rebound. Thus, the balance of available studies clearly supports the conclusion that Foxn1 plays a critical role in most if not all TEC differentiation and is a major regulator of the thymic microenvironment throughout the lifespan.