Mutant mice treated with tamoxifen showed total or near-total regeneration of their youthful thymus, while control mice also given tamoxifen showed predictable thymus function for their age. This held true for both the size of the organ itself and the abundance of the T-cells it produces. The regeneration seems to arise from the fact that FOXN1 is a transcription factor that controls expression of several other genes, and that these genes activate stem cell-like action in some thymus cells. By restoring FOXN1 levels, the researchers seem to have convinced the thymus to de-age itself — at least, in this one very specific way.
The researchers are quick to point out the possible benefits to elderly people, or those afflicted by immune diseases. Increasing the ability to fight infection could also revolutionize hospital medicine, helping vulnerable patients fight infection by “overclocking” the thymus to produce a boost of white blood cells. Restoring the immune response of sick and elderly people would be, without an ounce of hyperbole, one of the most important medical advances in all of human history.
Thymic involution is central to the decline in immune system function that occurs with age. By regenerating the thymus, it may therefore be possible to improve the ability of the aged immune system to respond to novel antigens. Recently, diminished expression of the thymic epithelial cell (TEC)-specific transcription factor Forkhead box N1 (FOXN1) has been implicated as a component of the mechanism regulating age-related involution. The effects of upregulating FOXN1 function in the aged thymus are, however, unknown. Here, we show that forced, TEC-specific upregulation of FOXN1 in the fully involuted thymus of aged mice results in robust thymus regeneration characterized by increased thymopoiesis and increased naive T cell output. We demonstrate that the regenerated organ closely resembles the juvenile thymus in terms of architecture and gene expression profile, and further show that this FOXN1-mediated regeneration stems from an enlarged TEC compartment, rebuilt from progenitor TECs. Collectively, our data establish that upregulation of a single transcription factor can substantially reverse age-related thymic involution, identifying FOXN1 as a specific target for improving thymus function and, thus, immune competence in patients. More widely, they demonstrate that organ regeneration in an aged mammal can be directed by manipulation of a single transcription factor, providing a provocative paradigm that may be of broad impact for regenerative biology
Upregulation of a crucial regulator of TEC differentiation, FOXN1, is sufficient to drive regeneration of the aged thymus such that it closely resembles the juvenile, pre-involution thymus in terms of architecture, gene expression and functionality. This FOXN1-mediated thymus regeneration results in improved thymic output in aged mice, with increased numbers of naive T cells exported to peripheral lymphoid organs. Collectively, our data demonstrate that the major impacts of age-related involution on thymus structure and function can be substantially reversed by restoring FOXN1 function, establishing that loss of FOXN1 expression is the principal cause of these components of thymic involution. They further provide insight into the mechanisms by which FOXN1 mediates thymus regeneration.
The findings contrast with the outcome of provoking thymus regeneration via sex-steroid ablation, which a recent study has shown results in transient generation of an enlarged, but phenotypically old thymus with no change in TRA expression or medullary complexity, and no upregulation of key regulatory and functional genes compared with aged controls (Griffith et al., 2012). In addition, most of the genes involved in the Wnt signaling pathway that were examined herein were downregulated during age-related thymic involution, in agreement with a previous study (Griffith et al., 2012). These genes were restored to young expression levels upon upregulation of FOXN1 activity in aged TECs, whereas their expression is not restored following sex steroid ablation-mediated rebound (Griffith et al., 2012). In vivo manipulation of FOXN1 expression, which not only enlarges the aged thymus but also restores its function, therefore presents a promising alternative strategy for clinical thymus regeneration – for instance by small molecule manipulation of signaling pathways that regulate FOXN1 expression or directly augment FOXN1 function.