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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