The Impact of Aging on CD4 T Cell Function
S. Swain
Trudeau Institute, Saranac Lake, NY 12983, USA
As people age their ability to be successfully immunized by vaccination
declines. We have found that the ability of naïve CD4 T cells to
respond and develop into effector and memory cells declines markedly
with age. To analyze the extent of the CD4 defect, we have used an
adoptive transfer model so that we can focus on the defect in the naïve
T cell population. We transfer T cell receptor transgenic naïve T cells
from aged mice into young T depleted hosts and examine the response of
the aged donor T cells compared young T cells.
The responding aged naïve cells are slower to initiate division, expand
less and make less IL-2 during their response in response to peptide
and ALUM. They also provide little help to host B cells, resulting in
dramatically reduced antibody. Ex vivo however, we find that addition
of IL-2 or proinflammatory cytokines (IL-1, IL-6 and TNFalpha) can
induce the aged naïve cells to become effectors and enhancement is also
seen in vivo when inflammatory mix is added.
Despite the restoration of effector generation, memory cells generated
from "restored" aged effectors are poor producers of cytokines and do
not proliferate well in response to recall stimulation. Importantly, if
memory is generated from young naïve CD4 T cells and then evaluated
after "aging", it is still intact.
The defect in function of aged naïve cells is not seen in bone
marrow-derived precursors of T cells and in fact aged precursors can
develop into functional naïve CD4 T cells even in aged mice. This led
us to postulate that the aging defect in the naïve cells may be a
consequence of their post-thymic longevity. In support of this
hypothesis, the aging defect develops more quickly when mice are
thymectomized. We have found that as mice age, the rate of homeostatic
division of naïve T cells increases. To test if such division
contributes to the defect, we transfer young naïve T cells to hosts
where they do or do not undergo such division and then evaluate their
function. The cells that have recently divided, make less IL-2 and
expand less when stimulated with antigen.
This suggests that accumulated homeostatic division may cause some of
the defects found in aged naïve T cells that are in turn in large part
responsible for the poor vaccination efficiency in the aged.
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