Mapping the Role of Foxn1 in Thymic Function

Researchers have of late been mapping the activities and relationships of Forkhead box protein N1 (Foxn1) in the thymus, and the paper I'll point out today outlines some of the most recent findings. Sadly it isn't open access, but I'm sure that won't stop the determined reader in this day and age. This work is of interest to our community of longevity science supporters because increased levels of Foxn1 have been shown to restore a more youthful level of thymic activity in older animals and human cell lines, and have been used to regrow thymic tissue when used in conjunction with cell therapies.

Why is thymic activity important? To simplify greatly, the thymus is where new T cells of the adaptive immune system mature after they are created. Its comparatively low level of activity in adults is one of the gating factors limiting the supply of new immune cells across most of the life span. Children have a very active thymus, and as a result a comparatively large supply of new immune cells, but the organ atrophies quite early in adulthood in a process known as thymic involution. Fat tissue replaces most of the structures that once nurtured immune cells and going forward an adult must get by with far fewer new immune cells. This low level of supply is one of the factors that effectively limits the size of the immune cell population in adults, and the fact that this population is limited eventually gives rise to a form of harmful resource misallocation. After a lifetime of exposure to pathogens, by the time old age arrives too many immune cells become focused on threats that cannot be cleared from the body, such as cytomegalovirus. When a large fraction of the limited population of cells become uselessly specialized in that way, too few cells are left to perform all of the other needed tasks: destroying cancerous and senescent cells, tackling unfamiliar pathogens, and so on.

The decline of the immune system is an important component of the frailty of aging, but this isn't just because old people become very vulnerable to infection. A failing immune system accelerates many of the other causes of aging. It produces greater chronic inflammation, as it is more active even as it is less able to do its job, contributing to a faster progression of near all of the common age-related diseases. The immune system is responsible for destroying senescent cells, which in larger numbers cause harm through the creation of inflammation and destruction of tissue structures. Fewer of these cells destroyed means more left to produce damage and dysfunction. Then there are potentially and actually cancerous cells, which have a greater chance of survival as the immune system becomes ever less effective. This is not to mention that the immune system plays a role in wound healing, as well as many other important processes. Given all of this, the goal of a restored immune system is a very important one, and even partially restoration should produce clear benefits.

One approach to this problem is to destroy the unwanted cells that are taking up space. Another approach is to deliver a much larger supply of new immune cells, such as directly via regular cell therapies, or alternatively through restoration of the thymus. There are a few different possible ways to restore the thymus. Transplantation has been shown to work in mice, producing improved immune function and extension of life, but that isn't going to work in human medicine since we'd want everyone to get a new thymus in old age. Tissue engineering is a strong possibility: researchers have made promising inroads towards the creation of thymic tissue. Then there is the use of Foxn1 to spur regrowth of the thymus, and this can even be mixed in with forms of cell therapy to grow thymic tissue within the patient rather than build outside the body and then transplant. Given the demonstrated importance of Foxn1, it is worth paying attention to research such the results noted here.

Study suggests routes to improved immunity in older people

Humans, like all higher animals, use T cells as part of the immune system, to fight off infections and cancer. T cells are generated in an organ called the thymus, where they closely interact with thymic epithelial cells (TEC) as they mature. People without TEC cannot generate T cells, severely compromising the immune system and consequently increasing the risk for life threatening infections and cancer. More than 20 years ago the transcription factor Foxn1 was identified as an essential molecule for the normal development of TEC. However, the genes directly controlled by Foxn1 - and thus responsible for the various TEC functions - have remained unidentified.

The researchers used new experimental models and analytical tools to investigate which genes were regulated by Foxn1 and how it affected them. Transcription factors bind to particular sections of our DNA and the team is the first to identify the DNA sequence bound by Foxn1. From there, they identified the hundreds of genes whose expression is regulated by this master regulator. These include genes that are essential to attract precursor cells in the blood, which are destined to become T-cells, to the thymus, genes that commit these precursor cells to become T cells and genes that provide the molecular machinery which allows the selection of those T cells that best serve an individual. Experiments in which Foxn1 expression by TEC was inhibited, confirmed that the transcription factor needs to be continuously present for TEC to function normally.

"The thymus is the organ in humans that first displays an age-dependent, physiological decline in function. It grows until puberty and then shrinks throughout the rest of our lives. This is thought to contribute to the decline in immunity in older people, which makes them more susceptible to opportunistic infections and cancers. The findings from these studies therefore provide important insight into the genetic control of regular TEC function and identify new potential strategies to preserve thymus function for longer, raising the prospect of a healthier old age."

Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells

Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1; however, its target genes have never been physically identified. Using static and inducible genetic model systems and chromatin studies, we developed a genome-wide map of direct Foxn1 target genes for the postnatal thymic epithelium and defined the Foxn1 binding motif. We determined the function of Foxn1 in these cells and found that, in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1.

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