The thymus is a small but vital internal organ. Thymocytes generated in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. One of the important contributions to the aging of the immune system is that the thymus steadily atrophies with advancing age, losing active tissue that is replaced with fat. This reduces the ongoing supply of replacement T cells to a fraction of the youthful numbers, leading to a adaptive immune system that is ever more populated by malfunctioning, exhausted, and senescent cells that should have been replaced - and ever more dysfunctional as a result. In most individuals, little thymic tissue is left by age 50, starting a slow countdown to the prevalent immunosenescence exhibited by people in their 70s.
A number of research groups and companies are now delving more deeply into the mechanisms governing atrophy of the thymus, tissue maintenance in the thymus, and regeneration of the thymus following injury. The hope is to find a cost-effective way to spur the atrophied, aged thymus into regrowth, and thus rejuvenate some aspects of the aged immune system. Sadly, much of the roadblock remains one of challenges in delivery and side-effects. There are demonstrated means of provoking thymus regeneration, but it is a small organ, and the only ways to bring materials to it efficiently remain direct injection and use of cells that home to the thymus. The former will never be approved for widespread use, because it carries a small but significant risk of severe side-effects in older people, and the latter will be too expensive for widespread use. Thus one needs a therapy that the rest of the body can tolerate or ignore, and so far the only viable means with evidence for modest thymic regrowth are (a) calorie restriction and (b) long-term growth hormone treatment combined with other drugs to blunt the side-effects of growth hormone.
Today's open access research is an interesting example of ongoing work on the mechanisms of thymic regeneration from injury. It remains unclear whether mechanisms identified in this context will also be useful in the context of normal tissue maintenance, however. The way to find out is to try, of course, and this work does at least point to one quite specific mechanism as a target.
Recirculating regulatory T cells mediate thymic regeneration through amphiregulin following damage
Robust thymic function produces a diverse T cell pool and is essential for a competent immune response. Decreased thymic output of T cells, resulting from age-associated thymic involution or thymic injury, increases the risk of malignancies, autoimmunity, mortality, and morbidity. There is an unmet clinical need to identify strategies to boost thymic function, particularly for patients undergoing cancer therapies and for older adults. The regenerative capacity of the thymus involves a complex interplay of stromal cells, innate immune cells, and immigrating bone-marrow-derived progenitor cells. The role of mature recirculating T cells in this process is poorly understood. However, recirculating regulatory T cells (Treg cells) have been identified as drivers of regeneration in specific compartments, such as lung, visceral adipose tissue, muscles, aorta, hair follicle, and skin - in addition to their classically understood roles in regulating adaptive and innate immune responses.
The cytokine amphiregulin (Areg) is specially implicated in the regenerative function of Treg cells at epithelial surfaces. In the thymus, a population of recirculating Treg cells that migrates between the periphery and the thymus coexists with newly generated Treg cells during negative selection. Here, we examined the role of Treg cells in the regeneration of the thymus after injury. We identified a unique population of Rag2GFP-CD4+Foxp3+ Treg cells that accumulate in the thymus after acute injury. Depletion and adoptive transfer of this cell population impaired and promoted, respectively, thymic repair in mice. Single-cell transcriptome analyses of this Treg cell population throughout aging highlighted variation in the expression of Areg, and Treg cell-specific deletion of Areg-impaired thymic regeneration. Analyses of human thymi identified a similar recirculating population of Treg cells. Our findings provide insight into the mechanisms of thymic regeneration and repair, with implications for therapeutic approaches aimed at boosting thymic function in the elderly and in cancer patients.
View the full article at FightAging
