Gain and Loss of T Cell Subsets in Old Age—Age-Related Reshaping of the T Cell Repertoire


The immune system is affected by the aging process and undergoes significant age-related changes, termed immunosenescence. Different T cell subsets are affected by this process. Alterations within the bone marrow and thymus lead to a shift in the composition of the T cell repertoire from naïve to antigen-experienced T cells, thereby compromising the diversity of the T cell pool. Additional infection with latent pathogens such as cytomegalovirus aggravates this process. In this review, we focus on the major age-related changes that occur in the naïve and the antigen-experienced T cell population. We discuss the mechanisms responsible for the generation and maintenance of these subsets and how age-related changes can be delayed or prevented by clinical interventions.


Worldwide the mean life expectancy is increasing and thereby leading to dramatic demographic changes. To ensure longevity and healthy aging the maintenance of appropriate immunity is necessary. However, as individuals age, numerous physiological functions are decreased, and the immune system undergoes profound age-related changes, termed immunosenescence. Changes of the aging immune system are of particular importance as they contribute to a higher incidence and severity of infectious diseases, decreased efficacy of vaccinations, and possibly autoimmunity and cancer [13]. Although immunosenescence affects many components of both, the innate as well as the adaptive immunity, the latter is more severely affected by aging. These changes are numerous and affect a wide range of cell types, ranging from hematopoietic stem cells and lymphoid progenitors to mature lymphocytes in secondary lymphoid organs and the periphery [4]. However, one of the most prominent features of immunosenescence and therefore mainly associated with the decline of immunological responsiveness in elderly persons are changes in the composition of the T cell compartment. The most substantial age-related changes within the T cell compartment are a decrease in the number of antigen-inexperienced naïve T lymphocytes combined with an increase in antigen-experienced memory and effector T cells. The initial trigger responsible for the dysbalance within the composition of the T cell pool observed in elderly persons is the involution of the T cell maturation organ, the thymus gland. Along with a decrease in functional thymic mass with age and the consequent reduction in naïve T cell output comes the necessity of homeostatic forces to take more responsibility assuming survival and in keeping T cell numbers constant. For the regulation of the maintenance of the T cell compartment, apoptosis is another key player since it controls the selection of the T cell repertoire in the thymus, the deletion of self-reactive lymphocytes, the regulation of immunological memory, and the deletion of effector T cells [5]. Further effects of aging on the immune system are telomere shortening, changes in T cell signaling, impaired DNA repair, and antioxidant mechanisms, which may all contribute in regulating T cell survival and shaping of the repertoire. Additionally, pathogens themselves may accelerate age-related changes. One prominent example that has been extensively studied in the context of immunosenescence is the cytomegalovirus (CMV) [6].

In this review, we describe the major age-related changes that occur in naïve versus antigen-experienced T cells. Specifically, we review the literature on the origin and fate of these subsets. Finally, we discuss modes of intervention potentially suitable to counteract deleterious changes.

Naïve T Cells

Age-Related Changes in the Generation of Naïve T Cells

All circulating blood cells of an individual including the mature lymphocytes originate from common pluripotent hematopoietic stem cells (HSCs), which are maintained in specialized niches within the bone marrow. Common T lymphoid progenitors leave the bone marrow in an immature state and migrate to the thymus, a central lymphoid organ responsible for the development, selection, and output of mature naïve T cells, referred to as recent thymic emigrants, into the periphery [7, 8]. One of the major changes in the aged immune system is a decline in the naïve T cell number. This has mainly two reasons: With age, the function of HSCs decreases due to deficiencies in DNA damage repair [9] and the shortening of telomeres [10], leading to a reduced capacity to generate lymphoid progenitors. It has also been suggested that age-related changes of the stem cell niche, e.g., the decline of the overall amount of hematopoietic tissue, can contribute to the declined HSC function in elderly persons [11]. Secondly, the thymus is severely affected. At birth, the thymus is fully developed, but its involution and the replacement of functional tissue by fat starts soon after birth, continues throughout life, and is almost complete at the age of 50 years [1214]. Thus, in young persons, naïve T cells are continuously generated and regenerate the T cell pool to retain the capability of the adaptive immune system to respond to a variety of different pathogens.

As a result of thymic involution, the output of peripheral naïve T cells is dramatically reduced (up to 80%) with age, which leads to a reduced ability of the host to respond to new antigens. Low naïve T cell numbers have been described in the periphery as well as lymphoid tissue [15, 16]. Recent striking evidence from young adults thymectomized as infants in the course of cardiac surgery who have decreased naïve T cell counts further emphasizes the role of the thymus for the maintenance of the naïve T cell repertoire [17, 18]. Similar results as in humans are reported in studies on mice. After thymectomy, the functionality of the already existing naïve CD4+ T cells is decreased, suggesting premature immune aging [19].

Maintenance of Naïve T Cells in Old Age

Aging affects the naïve CD4+ and CD8+ T cell compartments in slightly different ways [14, 2022]. Although the diversity and number of the naïve CD4+ T cell compartment is maintained stable for a long time, a dramatic and sudden collapse of diversity occurs after the age of 70 years, leading to a more restricted repertoire [23, 24]. Similar changes occur earlier in life and more gradually in the naïve CD8+ T cell compartment. In contrast to naïve CD4+ T cells, naïve CD8+ T cells of aged humans seem to be more susceptible to death receptor-mediated apoptosis, triggered by TNF-α or Fas [25, 26]. It is therefore suggested that Fas and TNF-α mediated apoptosis might contribute to the gradual disappearance of naïve, and also of memory, CD8+ T cells. Generally, the CD8+ T cell pool is more affected by age-related changes than the CD4+ T cell pool. This suggests that CD4+ T cells may be more prone to respond to survival-assuring mechanisms than CD8+ T cells.

The reduced thymic output of newly generated naïve T cells is compensated by several mechanisms. Homeostatic proliferation has been identified to play a key role for the maintenance and restoration of the size of the naïve T cell pool. Thus, it has been shown that IL-7 plays an essential role in controlling homeostatic proliferation of naïve CD4+ and CD8+ T cells and supports the survival of naïve CD8+ T cells [27]. For the survival of naïve CD4+ T cells, IL-7 and IL-4 are both essential [28]. It has been proposed that IL-7 acts in conjunction with TCR signals from contact with self-MHC/peptide ligands, which sustains the expression of anti-apoptotic molecules (e.g., Bcl-2). Naïve T cells are thus kept alive in a resting state and have a long lifespan [29, 30]. However, this extended lifespan is associated with a prolonged exposure of naïve T cells to unfavorable environmental factors, which cause DNA damage, which contribute to decreased function in old age [31]. If the naïve T cell numbers drop below 4% of total T cells, homeostatic proliferation increases exponentially. This accelerates telomere shorting and may lead to a memory-like phenotype [32, 33]. Naïve T cell survival may differ between subsets, as CD31+ (PECAM-1) thymic-naïve T cells decline during aging, but still display a polyclonal TCR repertoire, while central-naïve CD4+ CD31- T cell numbers remain constant during aging, but exhibit increased TCR-mediated signaling and a dramatically restricted TCR repertoire [34].

Age-Related Functional Changes of Naïve T cells

In humans, naïve T cells are defined on the basis of their surface expression of CD45RA, CD28, CD62L, or CCR7 [22, 35]. This population undergoes functional alterations during aging. For example, CD45RA+CD28+CD8+ T cells from elderly persons produce larger amounts of the pro-inflammatory cytokine IFN-γ after their stimulation with OKT3 and IL-2 than those cells of young persons [36]. They also have shorter telomeres and a highly restricted TCR repertoire compared with a corresponding population from young persons, suggesting increased homeostatic proliferation [37]. The loss of TCR diversity in the naïve T cell compartment has also been demonstrated in aged mice [38]. Studies in mice have also demonstrated that aged mice accumulate various intrinsic defects of naïve T cells related to TCR-mediated signaling, IL-2 production, and generation of long-term memory cells [39]. Thus, low IL-2 production leads, for instance, to reduced expansion and thereby to inefficient generation of effector T cells. This age-related defect can be reversed by the addition of exogenous IL-2 [3941]. Additionally, it has been shown that naïve CD4+ T cells do not form immunologic synapses upon stimulation with peptide antigen and antigen presenting cells [42]. This may be due to an altered cholesterol/phospholipid ratio in the lymphocyte membrane, leading to an impaired TCR-dependent recruitment of signal molecules to the immunological synapses [43, 44]. Impaired T cell surface glycosylation [45] and phosphorylation [4648] of key signaling molecules have also been suggested to contribute to age-associated defects in TCR signaling. Age-related defects in naïve T cell activation, expansion, and differentiation may affect their cognate helper function to B cells and lead to reduced humoral immune responses [49, 50].

Naïve T Cells in Vitro—Precautions

We and others have shown that the level of oxygen to which T cells are exposed is a critical parameter. Normally, cells in ex vivo and in vitro experiments are cultured in air supplemented with 20% O2, but, indeed, the oxygen level in the in vivo environment of T cells is lower than in the air and varies from 1% to 10 %, depending on the localization of the T cells [51, 52]. Recent studies have shown that different oxygen levels can influence the responsiveness of human T cells in vitro. Ex vivo T cell studies by Larbi et al. [53] showed a decreased proliferation and higher susceptibility to apoptosis at low oxygen levels following activation. These data could be confirmed by our group. We demonstrated that CD3/CD28-stimulated naïve T cells from young and elderly persons cultivated at 3% have a significantly increased rate of apoptosis (Fig. 1a) and reduced proliferation (Fig. 1b). It is therefore important to consider the oxygen levels in which naïve T cells are cultured in vitro when interpreting data from such experiments.

Fig. 1

Effect of oxygen level on apoptosis and proliferation of CD8+CD45RA+CD28+ T cells from young (n = 5) and elderly persons (n = 3), stimulated for 5 days with CD3/CD28 DynaBeads. a Flow cytometric analysis of Annexin V/7-AAD of CD8+CD45RA+CD28+ T cells at 3% and 20% oxygen after 5 days. A representative contour plot (left) and a bar chart (right; mean±SEM, *p < 0.05, Student’s t test). b Proliferation of CFSE-labeled CD8+CD45RA+CD28+ T cells at 3% and 20% oxygen after 5 days. One representative histogram is shown

In conclusion, naïve T cells display remarkable changes during aging, in number as well as in functionality.

Antigen-Experienced T cells

Generation of Memory T Cells

Immunological T cell memory is a key feature of the adaptive immune system in all vertebrates to ensure protection against previously encountered pathogens. Two models have been proposed for the generation of memory T cells following a primary infection. According to the first, linear, model, a naïve T cell is activated by its specific antigen and expands into an effector population that can potently eliminate the pathogen. After the infection has been cleared, the activated T cells enter a contraction phase which only some T cells survive and become memory T cells. [54]. The integration of various factors and environmental parameters, such as signal strength, costimulatory signals, and the surrounding cytokine milieu determines the outcome of the differentiation of an effector to a memory T cell. In stark contrast, the model of the asymmetric T cell division favors a more practical approach and a division of labor [55]. While a naïve T cell is primed by an antigen presenting cell, cytosolic and membrane components of the T cell shift and aggregate towards/away from the contact zone and remain throughout the first cell division. Unequal inheritance of those components to the progeny ensures the simultaneous generation of an effector cell, fully equipped with cytotoxic mediators at the proximal site of the immunological synapse, and a distal daughter cell that becomes the first memory T cell to that particular antigen.

Age-Related Changes within the Memory T Cell Compartment

During the course of healthy aging, the peripheral T cell compartment is populated by increasing numbers of memory T cells. This is due to the age-dependent decline in the output of naïve T cells (see above) and results in the filling of the resulting immunological space with naïve and memory T cells by homeostatic means. In contrast to naïve T cells, memory T cells rely on IL-7 in concert with IL-15, cycle and self-renew in vivo three- to fourfold faster than naïve T cells, and are capable of vigorous proliferation under lymphopenic conditions [56]. Additionally, homeostatic turnover of naïve CD8+ T cells may induce a memory-like phenotype [57, 58], thereby complicating the quantitative analysis of naïve, antigen-inexperienced T cells in elderly persons [22, 59]. In addition to the decrease in naïve T cell numbers, antigenic stimulation by persistent viral infections can challenge the tightly regulated orchestra of clonal expansion, contraction, and homeostasis of memory T cell and may thus lead to the massive accumulation of clones of certain specificities [60, 61]. This culminates in a dramatically reduced diversity of the memory T cell pool in elderly individuals [20, 24]. Similar to the situation in naïve T cells, this age-related effect is more pronounced within the CD8+ T cell compartment [62]. It is also of interest that new T cell subsets appear in the aged CD8+ memory compartment, such as a population of CD25+ T cells [59, 63]. These memory T cells, which are neither regulatory nor recently activated, produce IL-2 and IL-4 and represent an early stage in the differentiation of CD8+ T cells, with longer telomeres (indicating a shorter replicative history) and a polyclonal TCR repertoire. Elderly persons with a high frequency of CD8+CD25+ memory T cells seem to have a better functioning immune system as indicated by an intact humoral immune response after influenza vaccination.

Function and Maintenance of Memory T Cells

Similar to naïve T cells, where it has been shown that naïve T cells from young mice exhibit a better functional profile than naïve T cells from aged animals [40, 41], the functionality of memory T cells strongly depends on the age of the host at the time the antigen is encountered. Studies in mice have shown that CD4+ memory T cells generated during youth function well into old age, in vivo as well as in vitro, in terms of proliferation, cytokine production, and cognate helper function, compared with memory T cells generated later in life [64]. Once generated memory T cells have different possible destinies, they can survive as memory T cells, go into apoptosis, or differentiate into effector T cells. The homeostatic maintenance of memory T cells throughout lifetime is tightly regulated and preserves T cell repertoire diversity to combat new pathogens as well as the host’s ability to mount vigorous recall responses to recurrent infections [65]. Only recently have we begun to understand how and where memory T cells are maintained and sheltered in times of serenity. In this respect, the bone marrow and its mesenchymal stromal cells (MSCs) have been paid particular attention. Among other proteins, MSCs express proteoglycan ligands to CD44 which is present on memory T cells and mediates their local retention in the bone marrow. They furthermore produce IL-7 and IL-15 for the homeostatic maintenance of memory T cells [66]. It has been proposed that memory T cells, when in contact with stromal cells in the bone marrow, are suppressed and display reduced allogenic and mitogenic proliferation, a state of T cell anergy and reduced apoptosis as well as modulated cytokine production [66]. As for today, we only know little about the aged bone marrow and its role as survival niche for memory T cells. Recent data from our laboratory suggests that the bone marrow of elderly persons seems still intact as a frontline defense against recurrent infections (Herndler-Brandstetter et al., in preparation). Further sites of residence include the gut and other mucosal surfaces, which are not well-characterized in terms of age-related changes in the harboring potential of memory T cells. Further studies will have to shed light on how memory T cells are maintained throughout a lifetime, with special respect to these sites.

Generation of Terminally Differentiated T Cells

Over the last decade, scientific evidence has accumulated that persistent viral infections play a major role in driving the T cell compartment into exhaustion [6] with highest rates of exhausted T cells observed in elderly persons. Persistent infection with HCV [67], HIV [6873], and CMV [20, 74], but not EBV or VZV, have been shown to cause inflation of exhausted T cells already early in life. Depending on the type of persistent viral infection, T cells are repeatedly stimulated by viral antigens thereby contributing to the massive accumulation of virus-specific CD4+ and CD8+ T cell clones in both, mice [75], and humans [76, 77]. Although persistent CMV infection is systemically controlled by the immune system and viral particles are detectable only in times of reactivation, life-long exposure to CMV has been demonstrated to severely impair the T cell system. It increases the number of highly differentiated, exhausted CD4+ and CD8+ T cells [74, 78] with an average of 10%—in the elderly up to 50%—of the overall T cell pool being specific for CMV [77]. One of the most robust markers in describing these exhausted T cells is the lack of the costimulatory molecule CD28, a member of the tumor necrosis factor receptor family that interacts with CD80 and/or CD86 expressed on activated antigen presenting cells. Along with an appropriate TCR/MHC engagement, CD28 signaling provides the obligatory second stimulus to achieve full T cell activation and differentiation. Recently, it has been shown that signaling via the CD28 receptor overcomes the T cells auto-inhibitory pathway to sustain full T cell activation and IL-2 production [79]. The loss of CD28-mediated Akt (Ser473) signaling has also been associated with decreased telomerase activity [80] further contributing to the exhaustion of CD28- T cells. In general, the CD8+ T cell compartment is more affected by the accumulation of terminally differentiated T cells than the CD4+ T cell compartment [81, 82]. Exceptions represent rheumatoid arthritis and inflammatory bowel diseases, where the expansion of CD28- T cells is predominant in the CD4+ T cell compartment [83, 84].

Maintenance of Terminally Differentiated T Cells

The persistence and accumulation of exhausted T cells is still a matter of debate. Some reports using heavy glucose favor an extended lifespan rather than accelerated proliferation [85]. Along this line, other reports suggest a certain resistance to apoptosis [25, 26, 86]. Contrariwise, different authors stress their susceptibility to apoptosis [8789] and are therefore in favor of a more continuous production model, either antigenic-derived or homeostatically.

Functional Changes in Terminally Differentiated T Cells

The gene expression profile of CD8+CD28- T cells fundamentally differs from CD8+CD28+ T cells, both at the mRNA level as well as in microRNA usage, which in part explains the differences observed in apoptosis and the modulation of the activation threshold [9095]. The loss of CD28 is associated with a change of cellular function in T cells including decreased TCR-mediated activation and proliferation as well as a diminished ability to secrete IL-2 but high levels of cytotoxic mediators (perforin and granzymes) that enable them to exhibit immediate effector functions. The finding that CD28- T cells have shorter telomeres than their CD28+ counterparts [96, 97] completed the dogma of the “senescent” CD28- T cell arising from chronic TCR stimulation with no further proliferative capacity. Only recently have we begun to understand the complex processes taking place during the aging of the human immune system. It has been shown that CD28- T cells are not truly senescent as they can still proliferate if provided appropriate costimulation, especially by 4-1BBL and OX40L [98] and/or cytokines, such as IL-2 and IL-15 [87, 99].

Consequences of the Accumulation of Terminally Differentiated T Cells

The age-dependent accumulation of exhausted CD28- T cells, which preferentially produce the pro-inflammatory cytokines IFN-γ and TNF-α, is thought to contribute—together with components of the innate immune system—to the low-grade pro-inflammatory background observed in elderly persons (inflamm-aging) [100]. The enhanced prevalence of CD28- T cells in elderly persons, together with other parameters, such as a disturbed CD4/CD8 ratio and CMV-seropositivity, has led to the definition of the so-called “immune risk phenotype” predicting a higher 2-year mortality in a longitudinal study of octa- and nonagenarians [101]. The efficacy of booster vaccinations is severely decreased in the elderly [1, 102] and an insufficient antibody response following influenza vaccination in elderly persons has been correlated with a high frequency of CD8+CD28- T cells [103]. Persistent infection with CMV and the consequent accumulation of pro-inflammatory CD8+CD28- T cells have also been associated with an enhanced risk of coronary heart disease and impaired vascular function [104106]. In particular, vascular inflammation caused by vessel wall injury and endothelial cell dysfunction is triggered by persistent infection with CMV [107, 108] and leads to increased arterial blood pressure, consequently contributing to the development of atherosclerosis [109]. An accumulation of CD28- T cells was also identified in persons suffering from rheumatoid arthritis and ankylosing spondylitis [83, 110]. In conclusion, persistent infection with CMV and/or the accumulation of CD28- T cells may thus be involved in the pathogenesis of a broad variety of age-associated diseases.

Interventions to Decelerate Age-Related Changes of the T Cell Repertoire

Strategies to Counteract Age-Related Defects in Naïve T Cells

Experiments in mice [40] and studies in humans [111] indicate some promising approaches for the rejuvenation of naïve T cells leading to the production of new naïve T cells that function as well as young cells and better than those from aged individuals. Thus, it has been shown that the defects of old naïve T cells can be restored when IL-2-treated cells or naïve T cells from young mice are re-implanted into aged mice [49]. The production of rejuvenated naïve T cells can also be achieved by increasing immunological space by whole body irradiation [112]. Another strategy aims at restoring thymopoiesis in the elderly. Factors such as IL-7, growth hormone, and sex hormone ablation have thereby been tried (reviewed by [113]).

Caloric Restriction

Increasing lifespan of cells and organisms has long been of great interest for the scientific community. Caloric restriction (CR) is today the only known method to prolong median as well as maximal lifespan in all tested animals, from invertebrates to rodents and even vertebrates including non-human primates. While it is not fully understood how CR fulfills this life-prolonging effect, several probably concerted hypotheses have been postulated, one including the mTOR signaling pathway which we will discuss shortly hereafter. CR not only increases the median and maximal lifespan of a variety of organisms but also improves specific functions that seem to acquire failures with age, for instance the immune system. Nikolich–Zugich reviewed the impact of CR on the immune system and showed that in rodents and non-human primates CR was able to attenuate the natural shift from naïve to memory-phenotype T cells and maintain a higher number of naïve T cells in aged animals while decreasing the total number of peripheral lymphocytes [114]. Still, it remains unclear whether this is due to an increased thymic production of naïve T cells, improved maintenance of naïve T cells in the periphery, or reduced T cell activation. Furthermore, the age-related increase of pro-inflammatory cytokines, such as IL-6, IFN-γ, and TNF-α, and the resulting pro-inflammatory state of an aged immune system (inflamm-aging) can be reversed by CR. Finally, the decreased proliferative capacity of T cells in an aged immune system due to the shift from naïve to memory-phenotype T cells can be avoided and even retracted by CR.

mTOR, Autophagy, and Aging

The mammalian target of rapamycin (mTOR), a central integrator of diverse intra- and extracellular signals such as growth factors, nutrients, energy status, or stress signals [115] could be an explanation for the life-prolonging effect of CR. In case of sufficient nutrients and other positive signals and/or in the absence of stress signals, in other words, if the cell is doing fine, mTOR is active and thereby inhibits the catabolic process of autophagy while promoting anabolic processes important for growth and proliferation via different downstream molecules. Two of the best characterized ones are S6 kinase 1 (S6K1) and the 4E binding protein 1 (4EBP1) [116]. In the course of CR, nutrients are rare, and the enzymatic activity of mTOR is inhibited, leading to an upregulation of autophagy while cell growth and proliferation cease. This is reasonable for the cell since autophagy describes, among other things, the recycling of cellular components to gain new building blocks for critical proteins by degrading momentarily not needed proteins and even organelles [117]. It has been shown that autophagy can be induced in all somatic cells of an organism by fasting or CR which represents mTOR inhibition in the course of nutrient withdrawal [118]. It is known that chronological aging of cells leads to malfunctions in various cellular mechanisms, and autophagy is not an exception. It has been shown that with the aging of an organism, autophagic capacity declines, leading to the accumulation of already-quantitatively increased potentially harmful protein aggregates that are normally degraded via autophagy [118]. When in other somatic cells the autophagic efficiency declines with chronological aging, the same is certainly true for T cells. Interestingly, it has been found that in T cells that display replicative senescence characteristics, autophagic capacity is also decreased [119]. One might conclude that the higher the differentiation stage of a T cell is, the lower its autophagic capacity is and therefore its probability to survive stress situations.

Pharmacological Interventions

Besides CR, there are other methods to prolong lifespan via autophagy. Recently, we have shown that the natural polyamine spermidine promotes longevity in yeast, flies, worms, and human PBMCs in an autophagy-dependent fashion [120]. Furthermore, mice fed with a spermidine-rich diet have an increased lifespan [121]. Along the line of mTOR inhibiting autophagy, rapamycin, a well known inhibitor of mTOR and an immunosuppressive drug, prolongs lifespan in various organisms in a mTOR-dependent fashion [122124]. Interestingly, autophagy not only prolongs the lifespan but also increases the resistance to disadvantageous environmental circumstances [125]. In the immune system, mTOR is additionally responsible for the differentiation of CD8+ T cells. Araki et al. have recently shown that, in mice, inhibition of mTOR by rapamycin shortly after an acute lymphocytic choriomeningitis virus infection improved not only the quantity but also the quality of virus-specific CD8+ T cells [126]. Therefore, they propose that treatment with rapamycin after vaccination could enhance memory T cell formation.


Immunosenescence describes the wide range of changes within the immune system that occur with increasing age. In this review, we summarize the most prominent alterations in naïve and antigen-experienced T cells. Special emphasis is placed on terminally differentiated T cells that accumulate in the elderly, display a decayed functionality, and contribute to a low-grade pro-inflammatory background, a phenomenon called inflamm-aging. These age-associated dysfunctions within T cells have a strong clinical impact, the most important being reduced efficacy of vaccination and decreased resistance to infections. Our continuously improving comprehension of the aged immune system reveals strategies to overcome the detrimental effects of immunosenescence, some of which are discussed in this review.


  1. 1.

    Grubeck-Loebenstein B, Berger P, Saurwein-Teissl M, Zisterer K, Wick G. No immunity for the elderly. Nat Med. 1998;4(8):870.

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis. 2008;46(7):1078–84.

    PubMed  Article  Google Scholar 

  3. 3.

    Targonski PV, Jacobson RM, Poland GA. Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine. 2007;25(16):3066–9.

    PubMed  CAS  Article  Google Scholar 

  4. 4.

    Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol. 2004;5(2):133–9.

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Gupta S, Su H, Bi R, Agrawal S, Gollapudi S. Life and death of lymphocytes: a role in immunesenescence. Immun Ageing. 2005;2:12.

    PubMed  Article  Google Scholar 

  6. 6.

    Brunner S, Herndler-Brandstetter D, Weinberger B and Grubeck-Loebenstein B: Persistent viral infections and immune aging. Ageing Res Rev. 2010 (in press)

  7. 7.

    Kohler S, Thiel A. Life after the thymus: CD31+ and CD31− human naïve CD4+ T-cell subsets. Blood. 2009;113(4):769–74.

    PubMed  CAS  Article  Google Scholar 

  8. 8.

    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396(6712):690–5.

    PubMed  CAS  Google Scholar 

  9. 9.

    Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Natural. 2007;447(7145):725–9.

    CAS  Article  Google Scholar 

  10. 10.

    Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med. 2007;13(6):742–7.

    PubMed  CAS  Article  Google Scholar 

  11. 11.

    Wagner W, Horn P, Bork S, Ho AD. Aging of hematopoietic stem cells is regulated by the stem cell niche. Exp Gerontol. 2008;43(11):974–80.

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Steinmann GG. Changes in the human thymus during aging. Curr Top Pathol. 1986;75:43–88.

    PubMed  CAS  Google Scholar 

  13. 13.

    George AJ, Ritter MA. Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today. 1996;17(6):267–72.

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Aspinall R, Andrew D. Thymic involution in aging. J Clin Immunol. 2000;20(4):250–6.

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, et al. Shortage of circulating naïve CD8(+) T cells provides new insights on immunodeficiency in aging. Blood. 2000;95(9):2860–8.

    PubMed  CAS  Google Scholar 

  16. 16.

    Lazuardi L, Jenewein B, Wolf AM, Pfister G, Tzankov A, Grubeck-Loebenstein B. Age-related loss of naïve T cells and dysregulation of T-cell/B-cell interactions in human lymph nodes. Immunology. 2005;114(1):37–43.

    PubMed  CAS  Article  Google Scholar 

  17. 17.

    Prelog M, Keller M, Geiger R, Brandstatter A, Wurzner R, Schweigmann U, et al. Thymectomy in early childhood: significant alterations of the CD4(+)CD45RA(+)CD62L(+) T cell compartment in later life. Clin Immunol. 2009;130(2):123–32.

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Sauce D, Larsen M, Fastenackels S, Duperrier A, Keller M, Grubeck-Loebenstein B, et al. Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest. 2009;119(10):3070–8.

    PubMed  CAS  Article  Google Scholar 

  19. 19.

    Swain S, Clise-Dwyer K, Haynes L. Homeostasis and the age-associated defect of CD4 T cells. Semin Immunol. 2005;17(5):370–7.

    PubMed  CAS  Article  Google Scholar 

  20. 20.

    Weinberger B, Lazuardi L, Weiskirchner I, Keller M, Neuner C, Fischer KH, et al. Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly. Hum Immunol. 2007;68(2):86–90.

    PubMed  CAS  Article  Google Scholar 

  21. 21.

    Effros RB, Cai Z, Linton PJ. CD8 T cells and aging. Crit Rev Immunol. 2003;23(1–2):45–64.

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Pfister G, Weiskopf D, Lazuardi L, Kovaiou RD, Cioca DP, Keller M, et al. Naïve T cells in the elderly: are they still there? Ann NY Acad Sci. 2006;1067:152–7.

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Goronzy JJ, Lee WW, Weyand CM. Aging and T-cell diversity. Exp Gerontol. 2007;42(5):400–6.

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, et al. The influence of age on T cell generation and TCR diversity. J Immunol. 2005;174(11):7446–52.

    PubMed  CAS  Google Scholar 

  25. 25.

    Gupta S, Gollapudi S. TNF-alpha-induced apoptosis in human naïve and memory CD8+ T cells in aged humans. Exp Gerontol. 2006;41(1):69–77.

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Gupta S, Gollapudi S. CD95-mediated apoptosis in naïve, central and effector memory subsets of CD4+ and CD8+ T cells in aged humans. Exp Gerontol. 2008;43(4):266–74.

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo. Nat Immunol. 2000;1(5):426–32.

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Boursalian TE, Bottomly K. Survival of naïve CD4 T cells: roles of restricting versus selecting MHC class II and cytokine milieu. J Immunol. 1999;162(7):3795–801.

    PubMed  CAS  Google Scholar 

  29. 29.

    Caserta S, Zamoyska R. Memories are made of this: synergy of T cell receptor and cytokine signals in CD4(+) central memory cell survival. Trends Immunol. 2007;28(6):245–8.

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Tan JT, Dudl E, LeRoy E, Murray R, Sprent J, Weinberg KI, et al. IL-7 is critical for homeostatic proliferation and survival of naïve T cells. Proc Natl Acad Sci USA. 2001;98(15):8732–7.

    PubMed  CAS  Article  Google Scholar 

  31. 31.

    Barnett YA, Barnett CR. DNA damage and mutation: contributors to the age-related alterations in T cell-mediated immune responses? Mech Ageing Dev. 1998;102(2–3):165–75.

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Kilpatrick RD, Rickabaugh T, Hultin LE, Hultin P, Hausner MA, Detels R, et al. Homeostasis of the naïve CD4+T cell compartment during aging. J Immunol. 2008;180(3):1499–507.

    PubMed  CAS  Google Scholar 

  33. 33.

    Cicin-Sain L, Messaoudi I, Park B, Currier N, Planer S, Fischer M, et al. Dramatic increase in naïve T cell turnover is linked to loss of naïve T cells from old primates. Proc Natl Acad Sci USA. 2007;104(50):19960–5.

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Kohler S, Wagner U, Pierer M, Kimmig S, Oppmann B, Mowes B, et al. Post-thymic in vivo proliferation of naïve CD4+T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol. 2005;35(6):1987–94.

    PubMed  CAS  Article  Google Scholar 

  35. 35.

    Alves NL, Hooibrink B, Arosa FA, van Lier RA. IL-15 induces antigen-independent expansion and differentiation of human naïve CD8+T cells in vitro. Blood. 2003;102(7):2541–6.

    PubMed  CAS  Article  Google Scholar 

  36. 36.

    Pfister G, Savino W. Can the immune system still be efficient in the elderly? An immunological and immunoendocrine therapeutic perspective. Neuroimmunomodulation. 2008;15(4–6):351–64.

    PubMed  CAS  Article  Google Scholar 

  37. 37.

    Pawelec G, Akbar A, Caruso C, Effros R, Grubeck-Loebenstein B, Wikby A. Is immunosenescence infectious? Trends Immunol. 2004;25(8):406–10.

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Ahmed M, Lanzer KG, Yager EJ, Adams PS, Johnson LL, Blackman MA. Clonal expansions and loss of receptor diversity in the naïve CD8 T cell repertoire of aged mice. J Immunol. 2009;182(2):784–92.

    PubMed  CAS  Google Scholar 

  39. 39.

    Haynes L, Eaton SM. The effect of age on the cognate function of CD4+ T cells. Immunol Rev. 2005;205:220–8.

    PubMed  CAS  Article  Google Scholar 

  40. 40.

    Haynes L, Linton PJ, Eaton SM, Tonkonogy SL, Swain SL. Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naïve T cells of aged mice. J Exp Med. 1999;190(7):1013–24.

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Linton PJ, Haynes L, Klinman NR, Swain SL. Antigen-independent changes in naïve CD4 T cells with aging. J Exp Med. 1996;184(5):1891–900.

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Garcia GG, Miller RA. Age-dependent defects in TCR-triggered cytoskeletal rearrangement in CD4+ T cells. J Immunol. 2002;169(9):5021–7.

    PubMed  Google Scholar 

  43. 43.

    Huber LA, Xu QB, Jurgens G, Bock G, Buhler E, Gey KF, et al. Correlation of lymphocyte lipid composition membrane microviscosity and mitogen response in the aged. Eur J Immunol. 1991;21(11):2761–5.

    PubMed  CAS  Article  Google Scholar 

  44. 44.

    Stulnig TM, Buhler E, Bock G, Kirchebner C, Schonitzer D, Wick G. Altered switch in lipid composition during T-cell blast transformation in the healthy elderly. J Gerontol A Biol Sci Med Sci. 1995;50(6):383–90.

    Google Scholar 

  45. 45.

    Garcia GG, Miller RA. Age-related defects in CD4+ T cell activation reversed by glycoprotein endopeptidase. Eur J Immunol. 2003;33(12):3464–72.

    PubMed  CAS  Article  Google Scholar 

  46. 46.

    Miller RA, Garcia G, Kirk CJ, Witkowski JM. Early activation defects in T lymphocytes from aged mice. Immunol Rev. 1997;160:79–90.

    PubMed  CAS  Article  Google Scholar 

  47. 47.

    Kirk CJ, Freilich AM, Miller RA. Age-related decline in activation of JNK by TCR- and CD28-mediated signals in murine T-lymphocytes. Cell Immunol. 1999;197(2):75–82.

    PubMed  CAS  Article  Google Scholar 

  48. 48.

    Kirk CJ, Miller RA. Analysis of Raf-1 activation in response to TCR activation and costimulation in murine T-lymphocytes: effect of age. Cell Immunol. 1998;190(1):33–42.

    PubMed  CAS  Article  Google Scholar 

  49. 49.

    Eaton SM, Burns EM, Kusser K, Randall TD, Haynes L. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J Exp Med. 2004;200(12):1613–22.

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Haynes L, Maue AC. Effects of aging on T cell function. Curr Opin Immunol. 2009;21(4):414–7.

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167(11):6140–9.

    PubMed  CAS  Google Scholar 

  52. 52.

    Atkuri KR, Herzenberg LA, Niemi AK, Cowan T. Importance of culturing primary lymphocytes at physiological oxygen levels. Proc Natl Acad Sci USA. 2007;104(11):4547–52.

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Larbi A, Cabreiro F, Zelba H, Marthandan S, Combet E, Friguet B, et al. Reduced oxygen tension results in reduced human T cell proliferation and increased intracellular oxidative damage and susceptibility to apoptosis upon activation. Free Radic Biol Med. 2010;48(1):26–34.

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Seder RA, Ahmed R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat Immunol. 2003;4(9):835–42.

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science. 2007;315(5819):1687–91.

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    Surh CD, Sprent J. Regulation of naïve and memory T-cell homeostasis. Microbes Infect. 2002;4(1):51–6.

    PubMed  CAS  Article  Google Scholar 

  57. 57.

    Ge Q, Hu H, Eisen HN, Chen J. Naïve to memory T-cell differentiation during homeostasis-driven proliferation. Microbes Infect. 2002;4(5):555–8.

    PubMed  CAS  Article  Google Scholar 

  58. 58.

    Hamilton SE, Wolkers MC, Schoenberger SP, Jameson SC. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol. 2006;7(5):475–81.

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Herndler-Brandstetter D, Veel E, Laschober GT, Pfister G, Brunner S, Walcher S, et al. Non-regulatory CD8+CD45RO+CD25+ T-lymphocytes may compensate for the loss of antigen-inexperienced CD8+CD45RA+T-cells in old age. Biol Chem. 2008;389(5):561–8.

    PubMed  CAS  Article  Google Scholar 

  60. 60.

    Karrer U, Sierro S, Wagner M, Oxenius A, Hengel H, Koszinowski UH, et al. Memory inflation: continuous accumulation of antiviral CD8+T cells over time. J Immunol. 2003;170(4):2022–9.

    PubMed  CAS  Google Scholar 

  61. 61.

    Snyder CM, Cho KS, Bonnett EL, van Dommelen S, Shellam GR, Hill AB. Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity. 2008;29(4):650–9.

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Saule P, Trauet J, Dutriez V, Lekeux V, Dessaint JP, Labalette M. Accumulation of memory T cells from childhood to old age: central and effector memory cells in CD4(+) versus effector memory and terminally differentiated memory cells in CD8(+) compartment. Mech Ageing Dev. 2006;127(3):274–81.

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Schwaiger S, Wolf AM, Robatscher P, Jenewein B, Grubeck-Loebenstein B. IL-4-producing CD8+ T cells with a CD62L++(bright) phenotype accumulate in a subgroup of older adults and are associated with the maintenance of intact humoral immunity in old age. J Immunol. 2003;170(1):613–9.

    PubMed  CAS  Google Scholar 

  64. 64.

    Haynes L, Eaton SM, Burns EM, Randall TD, Swain SL. CD4 T cell memory derived from young naïve cells functions well into old age, but memory generated from aged naïve cells functions poorly. Proc Natl Acad Sci USA. 2003;100(25):15053–8.

    PubMed  CAS  Article  Google Scholar 

  65. 65.

    Nikolich-Zugich J. Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol. 2008;8(7):512–22.

    PubMed  CAS  Article  Google Scholar 

  66. 66.

    Tokoyoda K, Hauser AE, Nakayama T, Radbruch A. Organization of immunological memory by bone marrow stroma. Nat Rev Immunol. 2010;10(3):193–200.

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Gruener NH, Lechner F, Jung MC, Diepolder H, Gerlach T, Lauer G, et al. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol. 2001;75(12):5550–8.

    PubMed  CAS  Article  Google Scholar 

  68. 68.

    Pantaleo G, Soudeyns H, Demarest JF, Vaccarezza M, Graziosi C, Paolucci S, et al. Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection. Proc Natl Acad Sci USA. 1997;94(18):9848–53.

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Sewell AK, Price DA, Oxenius A, Kelleher AD, Phillips RE. Cytotoxic T lymphocyte responses to human immunodeficiency virus: control and escape. Stem Cells. 2000;18(4):230–44.

    PubMed  CAS  Article  Google Scholar 

  70. 70.

    Shankar P, Russo M, Harnisch B, Patterson M, Skolnik P, Lieberman J. Impaired function of circulating HIV-specific CD8(+) T cells in chronic human immunodeficiency virus infection. Blood. 2000;96(9):3094–101.

    PubMed  CAS  Google Scholar 

  71. 71.

    Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med. 2002;8(4):379–85.

    PubMed  CAS  Article  Google Scholar 

  72. 72.

    Kostense S, Vandenberghe K, Joling J, Van Baarle D, Nanlohy N, Manting E, et al. Persistent numbers of tetramer+CD8(+) T cells, but loss of interferon-gamma+HIV-specific T cells during progression to AIDS. Blood. 2002;99(7):2505–11.

    PubMed  CAS  Article  Google Scholar 

  73. 73.

    Oxenius A, Sewell AK, Dawson SJ, Gunthard HF, Fischer M, Gillespie GM, et al. Functional discrepancies in HIV-specific CD8+ T-lymphocyte populations are related to plasma virus load. J Clin Immunol. 2002;22(6):363–74.

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Almanzar G, Schwaiger S, Jenewein B, Keller M, Herndler-Brandstetter D, Wurzner R, et al. Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J Virol. 2005;79(6):3675–83.

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Mueller SN, Ahmed R. High antigen levels are the cause of T cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA. 2009;106(21):8623–8.

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, et al. Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol. 2005;175(12):8218–25.

    PubMed  CAS  Google Scholar 

  77. 77.

    Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202(5):673–85.

    PubMed  CAS  Article  Google Scholar 

  78. 78.

    Ouyang Q, Wagner WM, Zheng W, Wikby A, Remarque EJ, Pawelec G. Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly. Exp Gerontol. 2004;39(4):607–13.

    PubMed  CAS  Article  Google Scholar 

  79. 79.

    Bjorgo E, Tasken K. Novel mechanism of signaling by CD28. Immunol Lett. 2010;129(1):1–6.

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, et al. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol. 2007;178(12):7710–9.

    PubMed  CAS  Google Scholar 

  81. 81.

    Fagnoni FF, Vescovini R, Mazzola M, Bologna G, Nigro E, Lavagetto G, et al. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians. Immunology. 1996;88(4):501–7.

    PubMed  CAS  Article  Google Scholar 

  82. 82.

    Vallejo AN, Nestel AR, Schirmer M, Weyand CM, Goronzy JJ. Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity. J Biol Chem. 1998;273(14):8119–29.

    PubMed  CAS  Article  Google Scholar 

  83. 83.

    Schmidt D, Goronzy JJ, Weyand CM. CD4+ CD7- CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest. 1996;97(9):2027–37.

    PubMed  CAS  Article  Google Scholar 

  84. 84.

    Kobayashi T, Okamoto S, Iwakami Y, Nakazawa A, Hisamatsu T, Chinen H, et al. Exclusive increase of CX3CR1+CD28-CD4+ T cells in inflammatory bowel disease and their recruitment as intraepithelial lymphocytes. Inflamm Bowel Dis. 2007;13(7):837–46.

    PubMed  Article  Google Scholar 

  85. 85.

    Wallace DL, Masters JE, de Lara CM, Henson SM, Worth A, Zhang Y, et al. Human cytomegalovirus-specific CD8(+) T-cell expansions contain long-lived cells that retain functional capacity in both young and elderly subjects. Immunology. 2010;132:27–38.

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Gupta S, Gollapudi S. Susceptibility of naïve and subsets of memory T cells to apoptosis via multiple signaling pathways. Autoimmun Rev. 2007;6(7):476–81.

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Borthwick NJ, Lowdell M, Salmon M, Akbar AN. Loss of CD28 expression on CD8(+) T cells is induced by IL-2 receptor gamma chain signalling cytokines and type I IFN, and increases susceptibility to activation-induced apoptosis. Int Immunol. 2000;12(7):1005–13.

    PubMed  CAS  Article  Google Scholar 

  88. 88.

    Geginat J, Lanzavecchia A, Sallusto F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood. 2003;101(11):4260–6.

    PubMed  CAS  Article  Google Scholar 

  89. 89.

    Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Fann M, Chiu WK, Wood 3rd WH. Levine BL, Becker KG and Weng NP: Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev. 2005;205:190–206.

    PubMed  CAS  Article  Google Scholar 

  91. 91.

    Lindsay MA. microRNAs and the immune response. Trends Immunol. 2008;29(7):343–51.

    PubMed  CAS  Article  Google Scholar 

  92. 92.

    Lazuardi L, Herndler-Brandstetter D, Brunner S, Laschober GT, Lepperdinger G, Grubeck-Loebenstein B. Microarray analysis reveals similarity between CD8+CD28- T cells from young and elderly persons, but not of CD8+CD28+ T cells. Biogerontology. 2009;10(2):191–202.

    PubMed  CAS  Article  Google Scholar 

  93. 93.

    Weng NP, Akbar AN, Goronzy J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30(7):306–12.

    PubMed  CAS  Article  Google Scholar 

  94. 94.

    Hackl M, Brunner S, Fortschegger K, Schreiner C, Micutkova L, Muck C, et al. miR-17, miR-19b, miR-20a, and miR-106a are down-regulated in human aging. Aging Cell. 2010;9(2):291–6.

    PubMed  CAS  Article  Google Scholar 

  95. 95.

    Luo X, Tsai LM, Shen N, Yu D. Evidence for microRNA-mediated regulation in rheumatic diseases. Ann Rheum Dis. 2010;69 Suppl 1:i30–6.

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Monteiro J, Batliwalla F, Ostrer H, Gregersen PK. Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J Immunol. 1996;156(10):3587–90.

    PubMed  CAS  Google Scholar 

  97. 97.

    Kovaiou RD, Weiskirchner I, Keller M, Pfister G, Cioca DP, Grubeck-Loebenstein B. Age-related differences in phenotype and function of CD4+ T cells are due to a phenotypic shift from naïve to memory effector CD4+ T cells. Int Immunol. 2005;17(10):1359–66.

    PubMed  CAS  Article  Google Scholar 

  98. 98.

    Kober J, Leitner J, Klauser C, Woitek R, Majdic O, Stockl J, et al. The capacity of the TNF family members 4-1BBL, OX40L, CD70, GITRL, CD30L and LIGHT to costimulate human T cells. Eur J Immunol. 2008;38(10):2678–88.

    PubMed  CAS  Article  Google Scholar 

  99. 99.

    Chiu WK, Fann M, Weng NP. Generation and growth of CD28nullCD8+ memory T cells mediated by IL-15 and its induced cytokines. J Immunol. 2006;177(11):7802–10.

    PubMed  CAS  Google Scholar 

  100. 100.

    Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci. 2000;908:244–54.

    PubMed  CAS  Article  Google Scholar 

  101. 101.

    Chen WH, Kozlovsky BF, Effros RB, Grubeck-Loebenstein B, Edelman R, Sztein MB. Vaccination in the elderly: an immunological perspective. Trends Immunol. 2009;30(7):351–9.

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Chen WH, Kozlovsky BF, Effros RB, Grubeck-Loebenstein B, Edelman R, Sztein MB. Vaccination in the elderly: an immunological perspective. Trends Immunol. 2009;30(7):351–9.

    PubMed  Article  CAS  Google Scholar 

  103. 103.

    Saurwein-Teissl M, Lung TL, Marx F, Gschosser C, Asch E, Blasko I, et al. Lack of antibody production following immunization in old age: association with CD8(+)CD28(-) T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J Immunol. 2002;168(11):5893–9.

    PubMed  CAS  Google Scholar 

  104. 104.

    Blankenberg S, Rupprecht HJ, Bickel C, Espinola-Klein C, Rippin G, Hafner G, et al. Cytomegalovirus infection with interleukin-6 response predicts cardiac mortality in patients with coronary artery disease. Circulation. 2001;103(24):2915–21.

    PubMed  CAS  Google Scholar 

  105. 105.

    Grahame-Clarke C, Chan NN, Andrew D, Ridgway GL, Betteridge DJ, Emery V, et al. Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation. 2003;108(6):678–83.

    PubMed  Article  Google Scholar 

  106. 106.

    Spyridopoulos I, Hoffmann J, Aicher A, Brummendorf TH, Doerr HW, Zeiher AM, et al. Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity. Circulation. 2009;120(14):1364–72.

    PubMed  Article  Google Scholar 

  107. 107.

    Fish KN, Soderberg-Naucler C, Mills LK, Stenglein S, Nelson JA. Human cytomegalovirus persistently infects aortic endothelial cells. J Virol. 1998;72(7):5661–8.

    PubMed  CAS  Google Scholar 

  108. 108.

    Bentz GL, Yurochko AD. Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins. Proc Natl Acad Sci USA. 2008;105(14):5531–6.

    PubMed  CAS  Article  Google Scholar 

  109. 109.

    Cheng J, Ke Q, Jin Z, Wang H, Kocher O, Morgan JP, et al. Cytomegalovirus infection causes an increase of arterial blood pressure. PLoS Pathog. 2009;5(5):e1000427.

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Schirmer M, Goldberger C, Wurzner R, Duftner C, Pfeiffer KP, Clausen J, et al. Circulating cytotoxic CD8(+) CD28(-) T cells in ankylosing spondylitis. Arthritis Res. 2002;4(1):71–6.

    PubMed  Article  Google Scholar 

  111. 111.

    Holland AM, van den Brink MR. Rejuvenation of the aging T cell compartment. Curr Opin Immunol. 2009;21(4):454–9.

    PubMed  CAS  Article  Google Scholar 

  112. 112.

    Haynes L, Eaton SM, Burns EM, Randall TD, Swain SL. Newly generated CD4 T cells in aged animals do not exhibit age-related defects in response to antigen. J Exp Med. 2005;201(6):845–51.

    PubMed  CAS  Article  Google Scholar 

  113. 113.

    Hollander GA, Krenger W, Blazar BR. Emerging strategies to boost thymic function. Curr Opin Pharmacol. 2010;10(4):443–53.

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Nikolich-Zugich J, Messaoudi I. Mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol. 2005;40(11):884–93.

    PubMed  CAS  Article  Google Scholar 

  115. 115.

    Dunlop EA, Tee AR. Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms. Cell Signal. 2009;21(6):827–35.

    PubMed  CAS  Article  Google Scholar 

  116. 116.

    Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem. 2010;285(19):14071–7.

    PubMed  CAS  Article  Google Scholar 

  117. 117.

    Yang Z, Klionsky DJ. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12(9):814–22.

    PubMed  CAS  Article  Google Scholar 

  118. 118.

    Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A. Autophagy and aging: the importance of maintaining "clean" cells. Autophagy. 2005;1(3):131–40.

    PubMed  Article  Google Scholar 

  119. 119.

    Gerland LM, Genestier L, Peyrol S, Michallet MC, Hayette S, Urbanowicz I, et al. Autolysosomes accumulate during in vitro CD8+ T-lymphocyte aging and may participate in induced death sensitization of senescent cells. Exp Gerontol. 2004;39(5):789–800.

    PubMed  CAS  Article  Google Scholar 

  120. 120.

    Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11(11):1305–14.

    PubMed  CAS  Article  Google Scholar 

  121. 121.

    Soda K, Dobashi Y, Kano Y, Tsujinaka S, Konishi F. Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp Gerontol. 2009;44(11):727–32.

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    Kaeberlein M. Burtner CR and Kennedy BK: Recent developments in yeast aging. PLoS Genet. 2007;3(5):e84.

    PubMed  Article  CAS  Google Scholar 

  123. 123.

    Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004;14(10):885–90.

    PubMed  CAS  Article  Google Scholar 

  124. 124.

    Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11(1):35–46.

    PubMed  CAS  Article  Google Scholar 

  125. 125.

    Vigne P, Tauc M, Frelin C. Strong dietary restrictions protect Drosophila against anoxia/reoxygenation injuries. PLoS ONE. 2009;4(5):e5422.

    PubMed  Article  CAS  Google Scholar 

  126. 126.

    Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, et al. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460(7251):108–12.

    PubMed  CAS  Article  Google Scholar 

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Correspondence to Beatrix Grubeck-Loebenstein.

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Christoph R. Arnold, Juliane Wolf, and Stefan Brunner contibuted equally to this study.

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Arnold, C.R., Wolf, J., Brunner, S. et al. Gain and Loss of T Cell Subsets in Old Age—Age-Related Reshaping of the T Cell Repertoire. J Clin Immunol 31, 137–146 (2011).

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  • Immunosenescence
  • T cells
  • aging
  • human