Regulatory T cells and the immune aging process: a mini-review

Abstract

Constant exposure to new and persisting antigens and the need to replace cellular attrition with newly built cells lead to profound remodeling of the immune system after the age of 50 years. The impact of the immunosenescence process varies amongst the different cellular subsets represented within the immune system. Emerging data suggest that progressive aging significantly affects frequencies, subset distribution and functional competence of regulatory T cells (Tregs). Given the central role of Tregs in immune homeostasis, age-related loss of Treg function would be predicted to cause excessive immunity, encountered in elderly humans as a syndrome of chronic, smoldering inflammation as well as the age-related increase in the risk for autoimmunity. Conversely, age-dependent gain of Treg activity would result in failing immunity, such as the rising risk of malignancies and infections amongst the elderly. Emerging data suggest that some Treg populations, specifically naturally occurring Tregs, seem to accumulate with advancing age, whereas inducible Tregs appear to be less available in the older host. More studies are necessary to elucidate functional competence of old Tregs, with an emphasis on comparing the efficacy of young and old Tregs for defined functional domains. Mechanisms of declining Treg inducibility are not understood, but may provide an opportunity for targeted immunomodulation in the elderly. On the horizon is the potential to develop novel therapeutic interventions that target Tregs to make the elderly more efficient in fighting cancers and infections and dampen the risk for senescence-associated inflammation.

Figure 1. Natural Tregs accumulate with age while inducible Treg numbers decline

The frequency and absolute number of naturally occurring Tregs (both CD4⁺ and CD8⁺) increases with advancing age in both humans and mice. In contrast, the inducibility of Tregs from non-regulatory CD4⁺ and CD8⁺ precursor cells declines over time.

Figure 2. The impact of aging on the different functional domains of Tregs

Tregs isolated from young hosts are able to efficiently suppress APC activation, T cell proliferation and production of cytokines (IFN-γ, IL-2 and IL-17). Aged Tregs maintain suppressive activity towards APCs, T cell proliferation and IFN-γ production; whereas such aged Tregs are much less efficient in downregulating IL-2 and IL-17 production in neighboring T cells.