Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation.

Declines in immune function are well described in the elderly and are considered to contribute significantly to the disease burden in this population. Regulatory T cells (T(regs)), a CD4(+) T cell subset usually characterized by high CD25 expression, control the intensity of immune responses both in rodents and humans. However, because CD25 expression does not define all T(regs), especially in aged hosts, we characterized T(regs) by the expression of FOXP3, a transcription factor crucial for T(reg) differentiation and function. The proportion of FOXP3(+)CD4(+) T(regs) increased in the blood of the elderly and the lymphoid tissues of aged mice. The expression of functional markers, such as CTLA-4 and GITR, was either preserved or increased on FOXP3(+) T(regs) from aged hosts, depending on the tissue analyzed. In vitro depletion of peripheral T(regs) from elderly humans improves effector T cell responses in most subjects. Importantly, T(regs) from old FoxP3-GFP knock-in mice were suppressive, exhibiting a higher level of suppression per cell than young T(regs). The increased proportion of T(regs) in aged mice was associated with the spontaneous reactivation of chronic Leishmania major infection in old mice, likely because old T(regs) efficiently suppressed the production of IFN-gamma by effector T cells. Finally, in vivo depletion of T(regs) in old mice attenuated disease severity. Accumulation of functional T(regs) in aged hosts could therefore play an important role in the frequent reactivation of chronic infections that occurs in aging. Manipulation of T(reg) numbers and/or activity may be envisioned to enhance the control of infectious diseases in this fragile population.