We investigated the effects of aging on the IL-7-mediated CD8 ؉ T-cell survival pathway and of IL-7 therapy on T-cell immunity. Cells expressing IL-7 receptor (IL-7R) ␣ high and ␣ low were identified in a CD45RA ؉ effector memory (EM CD45RA؉ , CD45RA ؉ CCR7 ؊ ) CD8 ؉ T-cell subset. Elderly subjects (65 years and older) had an increased frequency of EM CD45RA؉ IL-7R␣ low CD8 ؉ T cells, leading to decreased STAT5 phosphorylation and survival responses to IL-7 compared with young subjects (40 years and younger). These EM CD45RA؉ IL-7R␣ low cells were largely antigen experienced (CD27 ؊ CD28 ؊ ), replicatively senescent (CD57 ؉ ), and perforin high CD8 ؉ T cells that had decreased IL-7R␣ mRNA, independent of guanine and adenine binding protein ␣ (GABP␣) and growth factor independence-1 (GFI1) expression. In measuring T-cell receptor (TCR) repertoires of EM CD45RA؉ CD8 ؉ T cells, the elderly had a limited repertoire in IL-7R␣ high and IL-7R␣ low cells, whereas the young had a diverse repertoire in IL-7R␣ high but not in IL-7R␣ low cells. These findings suggest that aging affects IL-7R␣ expression by EM CD45RA؉ CD8 ؉ T cells, leading to impaired signaling and survival responses to IL-7, and that IL-7 therapy may improve the survival of EM CD45RA؉ CD8 ؉ T cells with a diverse TCR repertoire in the young but not in the elderly. IntroductionThe proper development and maintenance of naive and memory CD8 ϩ T cells are essential for host defense. 1,2 IL-7, a member of the common cytokine-receptor ␥-chain (␥c) family, is critically implicated in the generation and maintenance of naive and memory CD8 ϩ and CD4 ϩ T cells. 3-8 IL-7 is produced by multiple stromal tissues, including epithelial cells in the thymus and bone marrow. 7 The IL-7R complex consists of 2 chains, the high-affinity IL-7R␣ chain and ␥c. 9 IL-7 binding to the receptor induces sequential phosphorylation of Jak1, Jak3, and STAT5, leading to the upregulation of Bcl-2, which promotes cell survival. 10,11 IL-7 regulates peripheral homeostasis of CD4 ϩ and CD8 ϩ T cells by promoting cell survival. When CD8 ϩ T cells from IL-7R intact and knockout (KO) mice were adoptively transferred to wild-type mice, cells from IL-7R KO mice had decreased survival compared with those from IL-7R intact mice. 3 Furthermore, in mice infected with lymphocyte choriomeningitis virus, IL-7R␣ high CD8 ϩ T cells had better survival and differentiation into memory cells than IL-7R␣ low CD8 ϩ T cells. 5 Alterations in T-cell immunity occur with aging. These alterations include thymic atrophy and changes in T-cell subsets and function, which likely contribute to increased risk for infection in the elderly. 12,13 For example, in 1998, 82 989 deaths in persons 65 and older in the United States were attributed to influenza and pneumonia, compared with 5969 deaths in persons aged 15 to 64. 14 In addition, CD4 ϩ and CD8 ϩ T-cell responses to the influenza vaccine were decreased in elderly subjects compared with young subjects. 15,16 Although the underlying mechanism for altered T-cell immune r...

We investigated the relationship of memory CD4+ T cells with the evolution of influenza virus-specific CD4+ T cell responses in healthy young and elderly people. Elderly individuals had a similar frequency of CD69+CD4+ T cells producing IFN-γ and TNF-α at 1 wk, but a lower frequency of these CD4+ T cells at 3 mo after influenza vaccination. Although the elderly had a higher frequency of central memory (CM; CCR7+CD45RA−) CD4+ T cells, they had a significantly lower frequency of effector memory (EM; CCR7−CD45RA−) CD4+ T cells, and the frequency of the latter memory CD4+ T cells positively correlated with the frequency of influenza virus-specific CD69+CD4+ T cells producing IFN-γ at 3 mo. These findings indicate that the elderly have an altered balance of memory CD4+ T cells, which potentially affects long term CD4+ T cell responses to the influenza vaccine. Compared with the young, the elderly had decreased serum IL-7 levels that positively correlated with the frequency of EM cells, which suggests a relation between IL-7 and decreased EM cells. Thus, although the healthy elderly mount a level of CD4+ T cell responses after vaccination comparable to that observed in younger individuals, they fail to maintain or expand these responses. This failure probably stems from the alteration in the frequency of CM and EM CD4+ T cells in the elderly that is related to alteration in IL-7 levels. These findings raise an important clinical question about whether the vaccination strategy in the elderly should be modified to improve cellular immune responses.

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Objective: Alterations in the immune system occur with aging, and these contribute to an increased risk of infection and malignancy. The age-associated changes in T cell immunity range from single cell function to the maintenance of cell populations. We investigated the kinetics of CD4 ＋ T cell activation and proliferation in young and elderly subjects after stimulating their peripheral blood mononuclear cells with anti-CD3 and anti-CD28 antibodies (Abs).Methods: The expressions of the activation markers CD69, CD40L and CD25 on the CD4 ＋ T cells from young (n=14) and elderly (n=19) were analyzed at 6, 24 and 48 hours (hrs) of T cell receptor (TCR) stimulation by using flow cytometry. In the same individuals, the CD4 ＋ T cell proliferation was determined at 48 and 96 hrs of TCR stimulation by using the CFSE dilution method. Results: The elderly had decreased CD69 and CD40L expressions on the CD4 ＋ T cells at 6 hrs of stimulation, as compared to that of the young patients. The elderly also had a decreased CD25 expression on the CD4 ＋ T cells at 24 hrs of stimulation. However, the two groups had similar levels of the CD25, CD69 and CD40L expressions at 48 hrs of stimulation. The elderly had decreased CD4 ＋ T cell proliferation at 96 hrs of stimulation, as compared to that of the