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Evidence for Aging of the Thymus to have a More Subtle Detrimental Effect on the Immune System than Thought

The T cells of the adaptive immune system are created in the bone marrow by hematopoietic stem cells, but migrate to the thymus to mature. Both the stem cell population and the thymus decline with age, reducing the rate at which new immune cells arrive to take up the fight against pathogens and potentially cancerous cells. This reduced rate contributes to the age-related failure of the immune system, as misconfigured and damaged cells start to accumulate more rapidly than they can be replaced with fresh, functional cells. The open access paper here presents evidence to suggest that the effects of thymic decline are more subtle than simply an across the board reduction in the rate at which new T cells are supplied, however.

Both of these proximate causes of immune system aging might be addressed in the years ahead. There are several lines of research into thymic regrowth, such as through tissue engineering or delivery of FOXN1. Meanwhile the field of stem cell research should arrive at ways to invigorate old and declining stem cell populations, both replacing damaged cells with new cells, and reverting the stem cell niche changes that cause stem cells to become less active in later life.

Chronic inflammation in the elderly is partially attributed to atrophy of the thymus - an organ that regulates the immune system - and in particular the ability of organisms to recognize their own cells-a phenomenon known as central tolerance. Immune central tolerance is established by two processes: first, immune cells that react strongly to self are eliminated in a process called negative selection, and second, thymic regulatory T (tTreg) cells are generated to suppress self-reactive immune reactions. The former has already been reported to be defective in the aged thymus, but whether the generation of new tTreg cells is also impaired has remained unclear.

Here, we analyzed the effect of aging on tTreg cell generation and found that the atrophied thymus is still able to make new tTreg cells; indeed, we show that tTreg cell generation capacity is enhanced when compared with other naïve T cells from the same thymus. We conclude that the balance of defective negative selection with enhanced tTreg cell generation may be necessary to avoid autoimmune diseases during aging.

Both negative selection and tTreg cell generation are critically dependent on medullary thymic epithelial cell (mTEC)-presentation (promiscuous expression) of self-antigens/peptides. Changes with age are potentially attributed to decreased T cell receptor (TCR) signaling strength due to inefficiency in promiscuous expression of self-antigens or presenting a neo-self-antigen by medullary thymic epithelial cells, displaying decreased negative selection-related marker genes (Nur77 and CD5high) in CD4 single positive (SP) thymocytes. Our results provide evidence that the atrophied thymus attempts to balance the defective negative selection by enhancing tTreg cell generation to maintain central T-cell tolerance in the elderly. Once the balance is broken, age-related diseases could take place.

Link: https://doi.org/10.1371/journal.pbio.2003352

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