The key cells of the adaptive immune system – CD4 T cells,
CD8 T cells and B cells – are each divided into two vast pools in the body:
naïve cells, which have not yet encountered an antigen to respond to, and
memory cells, which are descendents of naïve cells that met an antigen and
responded to it sometime in the past. As people age, naïve cell numbers decline
and memory responses to the many different pathogens encountered over a
lifetime accumulate. In addition to the decline in naïve cell numbers, there is
evidence that remaining cells become less functionally competent in older
individuals due to increased cell division (as less naïve cells are produced,
extant cells divide more to maintain numbers).
Two recent papers discuss age-associated changes in naïve T
cell homeostasis in the context of HIV infection and elderly uninfected
individuals. Tammy Rickabaugh and Beth Jamieson note the striking similarity
between the effects of HIV infection and aging on naïve T cell pools and
hypothesize that this “may play a role in the development of age-inappropriate
diseases in HIV-1+ individuals and contribute to poorer clinical outcomes
observed in the older HIV+ population.” Their research group at UCLA is
continuing to focus on this aspect of HIV pathogenesis.
In the pithily-named journal “Age,” Sara Ferrando-Martínez
and colleagues describe a comparison of thymic function and naïve T cell
parameters between individuals under 50 vs. over 50 years of age. The study is
unusual in that it recruited individuals undergoing cardiac surgery in order to
facilitate sampling of thymic tissue. The main findings echo data from mouse
models, showing that decreased thymic output of naïve T cells is associated
with increased proliferation of naïve T cells in the periphery. The increased
levels of naïve T cell division were in turn linked to higher expression of the
cellular senescence marker CD57 and shortened telomeres. The authors suggest
that not only declining naïve cell numbers but also loss of function may
contribute to poor immune responses in the elderly; however they stress that
additional studies will be needed to confirm or refute this hypothesis.
In terms of the therapeutic implications of this research,
Rickabaugh and Jamieson state: “Given the similarities in alterations of the
T-cell compartment with aging and HIV-1 infection, the development of
therapeutics to improve thymopoeisis, enhance peripheral T-cell function, and
prevent or delay senescence may prove to be beneficial to both affected
populations.”
Immunol Res. 2010 Aug 24. [Epub ahead of print]
A challenge for the future: aging and HIV infection.
Rickabaugh TM, Jamieson BD.
UCLA AIDS Institute and Department of Medicine, David Geffen
School of Medicine, University of California, 10833 Le Conte Ave, Mail Code
174521, Los Angeles, CA, 90095-1745, USA.
Abstract
Older individuals (>/=50 years of age) are increasingly
becoming a new at-risk group for HIV-1 infection and, together with those
surviving longer due to the introduction of anti-retroviral therapy (ART), it
is predicted that more than half of all HIV-1-infected individuals in the
United States will be greater than 50 years of age in the year 2015. Older
individuals diagnosed with HIV-1 are prone to faster disease progression and
reduced T-cell reconstitution despite successful virologic control with
anti-retroviral therapy (ART). There is also growing evidence that the T-cell
compartment in HIV-1(+) adults displays an aged phenotype, and HIV-1-infected
individuals are increasingly diagnosed with clinical conditions more commonly
seen in older uninfected persons. As aging in the absence of HIV infection is
associated with alterations in T-cell function and immunosenescence, the
combined impact of both HIV-1 infection and aging may provide an explanation
for poorer clinical outcomes observed in older HIV-1-infected individuals.
Thus, the development of novel therapeutics to stimulate immune function and
delay immunosenescence is critical and would be beneficial to both the elderly
and HIV-1-infected individuals.
Age (Dordr). 2010 Aug 11. [Epub ahead of print]
Age-related deregulation of naive T cell homeostasis in
elderly humans.
Ferrando-Martínez S, Ruiz-Mateos E, Hernández A, Gutiérrez
E, Rodríguez-Méndez MD, Ordoñez A, Leal M.
Laboratory of Immunovirology, Biomedicine Institute of
Seville (IBIS). Service of Infectious Diseases, Virgen del Rocío University
Hospital, Avda. Manuel Siurot s/n, 41013, Seville, Spain.
Abstract
Immunosenescence is characterized by phenotypic and
functional changes of effector memory T cells. In spite of the well-described
senescent defects of these experienced T cells, immune responses to new pathogens
are also deeply affected in elderly humans, suggesting that naive T cells could
also show age-related defects. It has been reported in both, animal models and
humans, alterations of the naive T cell turnover associated to advanced age or
low thymic function. However, as far as we know, homeostatic mechanisms
involved in the deregulation of naive T cell peripheral dynamics and their
consequences are still not well understood. Thus, the aim of our study was to
analyze homeostatic parameters of peripheral naive T cells and their
relationship with thymic function in young and elderly humans. Our results show
that lower naive T cell numbers were associated with a lower thymic function
and higher activation and proliferating naive T cell levels. We then analyzed
sjTREC numbers and relative telomere length from sorted naive T cells. Our
results show that the aberrant activation and proliferation status was related
to lower sjTREC numbers (a peripheral proliferation marker) and both, higher
CD57 expression levels and shortened telomeres (replicative senescence-related
markers). Elderly individuals show a greater contraction of the CD8 naive T
cell numbers and all homeostatic alterations were more severe in this
compartment. In addition, we found that low functional thymus show a CD4-biased
thymocyte production. Taken together, our results suggest a homeostatic
deregulation, affecting mostly the naive CD8 T cell subset, leading to the
accumulation of age-associated defects in, otherwise, phenotypically naive T cells.
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