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

CS Lages, I Suffia, PA Velilla, B Huang… - The Journal of …, 2008 - journals.aai.org
CS Lages, I Suffia, PA Velilla, B Huang, G Warshaw, DA Hildeman, Y Belkaid, C Chougnet
The Journal of Immunology, 2008journals.aai.org
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 …
Abstract
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-γ 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.
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