Declining expression of a single epithelial cell‐autonomous gene accelerates age‐related thymic involution

Abstract

SummaryAge-related thymic involution may be triggered by gene expression changes in lymphohematopoietic and ⁄ or nonhematopoietic thymic epithelial cells (TECs). The role of epithelial cell-autonomous gene FoxN1 may be involved in the process, but it is still a puzzle because of the shortage of evidence from gradual loss-of-function and exogenous gain-of-function studies. Using our recently generated loxP-floxed-FoxN1(fx) mouse carrying the ubiquitous CreER T (uCreER T ) transgene with a low dose of spontaneous activation, which causes gradual FoxN1 deletion with age, we found that the uCreER T -fx ⁄ fx mice showed an accelerated age-related thymic involution owing to progressive loss of FoxN1 + TECs. The thymic aging phenotypes were clearly observable as early as at 3-6 months of age, resembling the naturally aged (18-22-month-old) murine thymus. By intrathymically supplying aged wild-type mice with exogenous FoxN1-cDNA, thymic involution and defective peripheral CD4 + T-cell function could be partially rescued. The results support the notion that decline of a single epithelial cell-autonomous gene FoxN1 levels with age causes primary deterioration in TECs followed by impairment of the total postnatal thymic microenvironment, and potentially triggers agerelated thymic involution in mice.

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

“…The reduced expression or induced deletion of FOXN1 resulted in reduced TEC number and a disrupted thymic microenvironment [16,18,22,24,27]. Conversely, an intrathymic injection of FOXN1 cDNA-bearing plasmid into the thymus of aged mice or FOXN1 transgenic mice resulted in an increased number of TECs, leading to enhanced thymopoiesis and an increased naïve T-cell output [23,25]. These results indicate that FOXN1 has the potential to be used in the restoration or regeneration of TECs.…”

“…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.…”

“…Several studies have shown that TECs are sensitive to changes in FOXN1 dosage and that FOXN1 dosage can be neither insufficient nor excessive. For example, the mutant phenotype is dependent on FOXN1 genetic dosage [14,16,25]. Overexpression of FOXN1 by i.t.…”

“…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].…”

“…Overexpression of FOXN1 by i.t. administration of FOXN1 cDNA or transgeneic mice increased the number of TECs and enhanced thymopoesis [15,23,25]. However, highly overexpressed FOXN1 induced adverse effects on thymus development [14].…”