T cell subset-specific susceptibility to aging

Abstract

With increasing age, the competence of the immune system to fight infections and tumors declines. Age-dependent changes have been mostly described for human CD8 T cells, raising the question of whether the response patterns for CD4 T cells are different. Gene expression arrays of memory CD4 T cells yielded a similar age-induced fingerprint as has been described for CD8 T cells. In cross-sectional studies, the phenotypic changes were not qualitatively different for CD4 and CD8 T cells, but occurred much more frequently in CD8 T cells. Homeostatic stability partially explained this lesser age sensitivity of CD4 T cells. With aging, naïve and central memory CD8 T cells were lost at the expense of phenotypically distinct CD8 effector T cells, while effector CD4 T cells did not accumulate. However, phenotypic shifts on central memory T cells were also more pronounced in CD8 T cells. This distinct stability in cell surface marker expression can be reproduced in vitro. The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules.

Introduction

Failure of adaptive immunity with age is a major cause for morbidity and mortality in the elderly [1], [2]. As a highly dynamic organ, the immune system is in constant turnover, even in the absence of infections or obvious challenges with exogenous antigens [3]. Naïve T cells have a half-life of 6 to 12 months and memory T cells of 15 to 45 days [4], [5]. Thymic production of new T cells dwindles with age and does not meet the replenishment demand during adulthood [6], [7], [8]. After the ages of 40 to 50 years old, virtually the entire T-cell supply is generated from existing naïve and memory T cells [9]. In this setting, insufficient homeostatic mechanisms may lead to a progressive loss of naïve and memory T cells and contraction of T-cell receptor diversity [10], [11], [12], [13], [14]. In addition, the replicative stress associated with continuous turnover can induce cellular senescence and lead to phenotypic changes that impinge on the competence of the adaptive immune system [15], [16], [17], [18].

Both mechanisms contribute to failure to respond to new antigenic challenges, poor vaccine responses [19], [20], [21], [22] and increased morbidity with newly arising infections, such as is seen with antigenic shift or drift of the influenza virus [23], [24]. Moreover, memory T-cell responses to some persisting viruses wane—a prime example is the increased incidence of herpes zoster with age [25]. Epidemiological evidence suggests that signs of decreased immune competence first occur after the age of 50 and accelerate after the ages of 65 to 70 [20], [23], [25]. It is currently unclear which functional and phenotypic changes in the immune system occur at what ages and, in particular, whether different cell types are affected to distinct extents, possibly providing a model for the patterns of age-dependent susceptibilities for different viral infections.

Circumstantial evidence suggests that CD4 and CD8 T cells behave differently in response to aging. Oligoclonal expansions in the CD8 T-cell compartment can be readily detected with age and appear to be induced by chronic persisting viruses, in particular CMV, but also arise from uneven homeostatic proliferation [12], [15], [26], [27]. In contrast, oligoclonal expansions within the CD4 compartment are rare and preferentially found in patients with autoimmune diseases [28]; they do not reach the clonal size seen with CD8 T cells [18]. Even at the age of 65, decades after the involution of the thymus, both naïve and memory CD4 T cells are highly diverse and show no contraction in T-cell receptor diversity compared to young adults [10]. Also, the classical phenotypic change of CD28 loss, frequently encountered in CD8 T cells with age [17], is only inconsistently seen for CD4 T cells [11]. However, the molecular mechanisms regulating CD28 expression and loss appear to be identical in both T-cell subsets [29], [30], suggesting a fundamental difference in CD4 and CD8 T cells in response to aging, possibly in addition to distinct cell-specific transcriptional regulation. The objective of this study was to compare CD4 and CD8 T cells and to determine whether differences in their phenotypic response pattern to aging are explained by differences in T-cell subset homeostasis or whether CD4 and CD8 T cells are intrinsically different in controlling gene expression.