Fight Aging!

Regulatory T cells, as the name might suggest, are involved in controlling the immune response, particularly damping it down at the point at which it should resolve. They also prevent an inflammatory response from starting when it would be harmful or unnecessary, such as in response to self-antigens. A failure of regulatory T cell function is likely involved in autoimmunity, as well as in the chronic inflammation of aging.

As today's open access paper notes, regulatory T cells may be both harmful and helpful in older individuals, attempting to suppress inappropriate inflammation, but also becoming dysfunctional in ways that both suppress appropriate immune responses to infection and allow autoimmune conditions to arise by failing to suppress the response to self-antigens. Yet all too little of this is certain in the details, and published studies provide a wealth of entirely contradictory evidence. The paper notes studies that report, variously, that immune suppression by regulatory T cells is increased, decreased, or unchanged with age under various circumstances.

How does a class of immune cells responsible for suppressing inflammatory signaling and behavior manage to both over-suppress where inappropriate and under-suppress where inappropriate? Therein lies the question. The immune system is complicated, and no class of T cells is a single monolithic entity. Regulatory T cells have subtypes, while the effects of the surrounding environment on their behavior are just as complicated, situational, and distant from a full understanding as is the case for the rest of the immune system as a whole.

The dark side of Tregs during aging

From a holistic point of view, aging results from the progressive decline of various systems. Among them, the distinctive age-dependent changes in the immune system contribute to the enhanced frailty of the elderly. One of these affects a population of lymphocytes, known as regulatory T cells (Tregs), as accumulating evidence suggest that there is a significant increase in the frequency of these cells in secondary lymphoid organs of aged animals. Although there are still discrepancies in the literature about modifications to their functional properties during aging, mounting evidence suggests a detrimental role for Tregs in the elderly in the context of bacterial and viral infections by suppressing immune responses against non-self-antigens. Interestingly, Tregs seem to also contribute to the reduced effectiveness of immunizations against many pathogens by limiting the production of vaccine-induced protective antibodies

With regard to Treg immunosuppressive activity, there is still an open debate regarding whether these cells have increased or decreased functionality during aging, with evidence for both outcomes. However, there is also evidence from other studies that the suppressive activity of Tregs is not contingent on age, but instead is retained at nearly the same level throughout the lifespan. These studies showed that Tregs from young and aged mice as well as in humans have the same suppressive capacity since they can suppress CD4+ T cell proliferation to the same extent. On the other hand, Tregs from old mice have also been described as being better suppressors than those from young adult animals due to higher IL-10 production.

The most likely reason behind these inconsistencies and conflicting data is that CD25 does not accurately recapitulate Foxp3 expression and Treg activity in aged mice, so it may act as a confounding factor in the interpretation of suppression assays. Another major caveat regarding the use and interpretation of in vitro suppression assays is that they may not be truly representative of in vivo Treg-mediated suppression mechanisms. Results obtained through the use of anti-CD25 antibodies do not allow researchers to discriminate between the suppressive activity of CD4+ and CD8+ Tregs, which have also been reported to increase with age. Results can also be deeply influenced by the responder cells, which may change depending on the cell's age and type, as well as the stimuli they receive, independently of Treg functions. Moreover, the in vivo model used might affect Treg suppression, phenotype, and homing, depending on the unique local inflammatory environment.

Taken together, these conflicting data do not completely explain the simultaneously increased risk of autoimmunity, cancer, and infections observed in the elderly. Therefore, how the intrinsic functions of Tregs change during aging and what the impact of those changes may be remain questions yet to be elucidated.