Regeneration of the aged thymus by a single transcription factor

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.

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

“…This includes a reduction in thymopoiesis-supporting thymic epithelial cells (TECs) (10), an increase in fibroblasts (11,12), and emergence of adipocytes (4,13) of unknown origin and function. Accordingly, recent efforts have focused on targeting TECs for the rejuvenation of the aging thymus (12,14). Emerging evidence indicates that immunemetabolic interactions control several aspects of the thymic involution process and age-related inflammation (13).…”

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

“…It is generally acknowledged that FOXN1 is a pivotal regulator for TEC development [11][12][13][14][15][16][17][18][19]. Mice homozygous for loss-of-function mutation in FOXN1 display the 'nude' phenotype (FOXN1 nu/nu ), which is characterized by congenital athymia and hairlessness.…”

“…A mutation in the human FOXN1 gene also results in a nude phenotype [20,21]. 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].…”

“…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.…”

“…Although age-dependent thymic involution can be caused by both ETP and TEC degeneration, recent data have shown that a reduced expression or the deletion of a single gene, FOXN1, leads to phenotypes similar to age-dependent thymic involution. Moreover, overexpression of FOXN1 attenuates age-associated thymic involution [15,23,25]. It will be of much interest to determine whether rFOXN1 treatment can prevent or reverse age-dependent thymic involution.…”