More on FOXN1 in the Aging Thymus
Last year, researchers demonstrated restoration of youthful activity of the thymus in old mice via increased levels of FOXN1. Rejuvenation of the thymus is one possible path towards at least partial rejuvenation of the immune system, as its decline in adulthood limits the supply of new immune cells, and that limit is one of the factors that creates dysfunction and dysregulation of the immune system in old people. In this paper researchers further characterize the age-related decline in FOXN1 levels in the thymus:
In human, the thymus-derived naïve T cell repertoire, capable to exert effective protection to foreign antigens, is established during early embryonic life and it reaches maximal size in childhood, subsequently, as antigen specific T cells are generated, the naïve T cell pool is gradually depleted. Thus, the limited naïve T-cell repertoire in elderly individuals is a major contributor to age-related immunodeficiency, a frequent cause of death. The immune compromised status results in the lack of effective immune response against pathogenic microrganisms and malignant cells. Because age related immunodeficiency is often life limiting as the cause of frequent nosocomial infections of the elderly, and because current treatment is insufficient, moreover it represents a significant medico-economic burden, there is a strong interest to develop effective and economically sound therapies. One possible strategy is the restoration of the naïve T cell repertoire via therapeutic regeneration of thymic activity.
In humans, as the thymus ages, thymic epithelial mesh is gradually replaced by adipose tissue. The process is thought to start at the first year of life and continues during aging, being accompanied by a decreasing export of naive T cells. The underlying molecular mechanisms responsible for the impairment of thymopoiesis in the aging thymus remains unclear. One possibility is that intrinsic mechanisms related to thymic epithelial cells (TEC) physiology are impaired in old individuals, since bone marrow precursors from old animals are able to colonize the thymus.
Studies in rodent models pointed out that the transcriptional factor forkhead box protein N1 (FOXN1) is both necessary and seemingly sufficient to induce differentiation of functional TEC. For the first time, we report here a striking three-fold decrease of FOXN1 expression over time in the human thymus, when comparing the "Postnatal" group with the "Adult" group. In fact, the decrease of TEC associated expression levels may be markedly higher, as due to the relatively lower lymphocyte content of the aging thymus, the relative abundance of TEC is increasing. We thus suggest that FOXN1 expression may limit thymopoiesis and its reduced expression may be responsible for thymic senescence.
To model age-related changes, we tested a human thymus derived epithelial cell line, hTEC, for expression of FOXN1. One of the most important epigenetic mechanisms that is often involved in transcriptional regulation during development is CpG methylation. To investigate the methylation status of CpG residues in the FOXN1 gene in the hTEC, we tested a candidate regulatory region (we named C20). In the C20 candidate region FOXN1 expressing skin cells show minimal methylation in 8 of the 13 candidate CpGs of the C20 region, while FOXN1 non-expressing leukocyte is highly methylated. Overall methylation is decreasing with age, and hypermethylation of the C20 segment of the hTEC provides a strong clue supporting our hypothesis, namely that hypermethylation may gradually silence the FOXN1 ultimately leading to decreased thymopoesis.