Abstract
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.
Highlights
The thymus, the obligate site of T lymphocyte development (Miller, 1961), is one of the first organs to degenerate in normal healthy individuals (Chinn et al, 2012)
A transgenic model for conditional inducible Foxn1 expression To test the hypothesis that upregulation of Foxn1 in the aged, fully involuted thymus might reverse age-related thymic involution, we generated a transgenic mouse model that permits conditional, inducible overexpression of Foxn1, through production of a tamoxifen-inducible form of mouse Forkhead box N1 (FOXN1), FOXN1ERT2 (ROSA26CAG-STOP-Foxn1ERT2IRES-GFP mice, referred to as R26Foxn1ER; Fig. 1A; supplementary material Figs S1 and S2)
We have shown that upregulation of a crucial regulator of thymic epithelial cell (TEC) differentiation, FOXN1, is sufficient to drive regeneration of the aged thymus such that it closely resembles the juvenile, preinvolution thymus in terms of architecture, gene expression and functionality
Summary
The thymus, the obligate site of T lymphocyte development (Miller, 1961), is one of the first organs to degenerate in normal healthy individuals (Chinn et al, 2012) This process, termed ‘age-related thymic involution’, results in decreased production of naive T cells with age (Weng, 2006; Lynch et al, 2009; Chinn et al, 2012).
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