In a young healthy adult (<30 years of age) there are approximately 3 × 1011
T cells, of which 1–2% can be found within the blood, and up to 50% are within the antigen-naïve population. During a successful response, activation of these antigen-naïve T cells leads to their clonal expansion, the generation of effector cells and the subsequent reduction in the amount and source of the antigen. This is followed by a period of cell death since the immune system no longer requires large numbers of T cells bearing that specific antigen receptor; however, some cells remain and become memory T cells that subsequently enter the memory T cell pool. Repeated exposure of the immune system to a potential pathogen will be met by these memory T cells and will lead to a response that is more rapid and of greater magnitude than the response following the initial exposure. As there are few completely sterile environments, each of us is confronted on a daily basis with different organisms. Thus, our survival depends upon our immune system recognising and responding successfully to a broad range of potential pathogens. Provided these pathogens do not result in our death, our immunological memory should increase; indeed, analysis shows that aging is associated with an increase in the number of memory T cells. Theoretically then, with this increased memory T cell pool, we should be able to cope with more infections as we get older. Unfortunately this does not seem to be the case. Evidence from epidemiological, clinical and laboratory studies suggest an age-related defect in the immune system. The epidemiological evidence reveals that older individuals are often the first to be affected by new or emerging pathogens such as West Nile virus [11
]. During an epidemic of West Nile virus in the United States in 2002, the majority of cases occurred in those over 50 years of age. The epidemic caused 4156 cases, of which 284 were fatal; the median age of the deceased was 78 years of age [12
]. Clinicians recognise that in addition to this susceptibility to new pathogens, older individuals often have difficulties in dealing with pathogens which they have previously overcome, including the annual return of influenza. Although influenza infection is considered to be a self-limiting contagious viral-mediated disease of the respiratory tract, it is associated with considerable morbidity and mortality in the elderly. Those >65 years of age account for >90% of the deaths from influenza and are more likely to develop complications such as pneumonia following infection [13
Such age-associated dysfunctions are preceded by a measurable decline in thymic export of αβ+
T cells [14
] to the naïve T cell pool, which declines with age due to the combination of the limited lifespan of naïve cells, reduced thymic function, and recruitment of naïve cells into activated and memory T cell pools. Homeostatic mechanisms, however, ensure that numbers within the total T cell pool are maintained through life within specific limits, so a decrease in naïve T cell numbers is matched by an increase in the number of memory T cells [16
] and senescent T cells [18
The age-associated alteration in the number of naïve T cells emerging from the thymus is thought to be caused by changes in the thymic microenvironment that prevent thymopoiesis. One element recently implicated in these changes is interleukin-7 (IL-7) [19
]. IL-7 has a central role in the production of T cells. The receptor for IL-7, which comprises a common γ chain and an α chain, is expressed during the intrathymic T cell developmental pathway [20
]. Interaction between IL-7 and its receptor at early stages of the T cell pathway has been reported to aid cell survival [21
] and also act as a cofactor in recombination events [22
]. At later thymocyte stages, this interaction may act to expand positively selected thymocytes [23
]. An age-related reduction in production of IL-7 within the thymus [19
] contributes to the reduced survival of thymocytes [25
] and it is this reduction which produces the age-related decline both in thymic size and thymic output.
The decline in IL-7 expression levels makes it a target for therapeutic interventions to rejuvenate thymopoiesis in the elderly. Previous work has shown that IL-7 can reverse the atrophy of the thymus in old animals, ensuring increased thymic output to the peripheral T cell pool and improving immune responses [25
]. The normal therapeutic approach has been to inject IL-7 subcutaneously so that it will diffuse through the organs and tissues of the body to reach its target organ. This approach is inefficient because of the low concentration of IL-7 that eventually reaches the thymus. As with most therapeutic agents, there is likely to be a threshold IL-7 concentration requirement, below which it has no effect. The approach taken to overcome this problem was to target IL-7 to the thymus by the creation of a fusion protein. The molecule CCL25 is produced in the thymus [26
] and binds to the chemokine receptor CCR9 for which it is the only known ligand. A fusion protein between the extracellular portion of CCR9 and IL-7, when used as a therapeutic agent in old animals, results in the accumulation of the fusion protein in the thymus, the reversal of age-associated thymic atrophy, a significant increase in the production of new T cells and a significant improvement in antiviral responses in old animals [26
]. An example of the effect of the fusion protein treatment is provided in Figure which shows that mice treated with the fusion protein had a lower influenza viral load in their lungs, compared with sham-treated animals, following influenza infection.
Figure 2 Influenza viral load in the lungs of 20 month old mice, 6 days after infection. Copyright 2005 The American Association of Immunologists, Inc. *P< 0.001 when compared with the control group. These mice had expression plasmids containing either (more ...)
IL-7 clearly has an important role in thymic functioning and these findings indicate that modulation of IL-7 may offer a target for increasing the response to vaccination in the elderly.