CC BY
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UDK:619:612.017
Maslyanko R.P., Stoyanovsky V.G., Bozhyk L.Y., Romanovich M.S., Rapa O.I. ©
Lviv National University of veterinary medicine and biotechnologies named after S.Z. Gzhytsky
THE IMMUNE SYSTEM AND AGING
Aging of the immune system is associated with both a marker reduction on responsiveness as well as functional dysregulation. Aging presents the most incisive personal, medical, and socioeconomic problem in developed countries. In the present review, we first discuss molecular and cellular aspects of aging followed by a brief summary of the most popular examples for stochastic and deterministic theories of aging, respectively, and a description of general cellular age-dependent morphological and functional changes leading to the proper topic, i.e., the aging of the immune system.
In the elderly the incidence of severe infections is high and the protective effect of vaccination low. Furthermore, autoimmune reactivity increases with age. However, the mechanisms underlying age-related immune dysfunctions are far from being clear. As a matter of fact, there are few fields in immunology that are less controversial than immunosenescence. Reasons for these controversial observations are discussed with special emphasis on the difficulty to differentiate primary from secondary age-dependent alterations of immune reactivity, i.e., the latter developing due to underlying disease.
Although bone marrow progenitor cells seem to be little affected in old individuals, there is a significantly reduced ability of the microenvironment to support hematopoietic regeneration. The first indication of immunosenescence is the involution of the thymus entailing a loss of naive T cells in the periphery. The absence of the thymus is accompanied by continuous reactivation, clonal expansion, and elimination of memory effector T cells of various specificities leading to changes in the T-cell repertoire reflected by characteristic changes of lymphocyte subpopulations, e.g., a shift from the CD45RA+CD45RO- to the CD45RACD45RO+ subset in elderly humans and animals.
Telomere shortening is more pronounced in CD28- than in CD28+ cells from a donor, indicating that the former have undergone more rounds of cell division than the latter consistent with a state of terminal effector cell differentiation.
Key ords: immune system, macrophages, T lymphocytes, B lymphocytes, immunoglobulins, vaccination, aging
In the elderly, the incidence of severe infections is high and the protective effect of vaccination is low [1], both due to the fact that the function of the immune system declines with age. Although this is generally accepted, the exact nature of the underlying defects is far from clear. Intensive research over the past decades has attempted to clarify the basic mechanisms of age-related immune dysfunctions, but it has turned out to be a difficult task. Many published reports conflict in theoretically and practically important points. The production of the TH type-1 cytokine interferon-y (IFNy) has, for instance, been reported to be high, low, or unchanged during aging, and many similarly contradictory examples could be cited [2].
© Maslyanko R.P., Stoyanovsky V.G., Bozhyk L.Y., Romanovich M.S., Rapa O.I., 2014
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Controversial observations may result from variations among species, strains, organs, and culture systems, but may also be due to interindividual differences in the course of the biological aging process. The health status of elderly persons may also play a role in this respect. To identify "healthy" old probands and appropriate young controls, a working party of the European Economic Community "Concerted Action on Aging" (EURAGE) established the so-called SENIEUR protocol of selection criteria for immunogerontological studies [3]. This rather elaborate protocol takes into account (a) the living conditions of healthy volunteers, (b) laboratory values, and (c) drug intake. Still, even using the SENIEUR protocol, a high degree of controversy on substantial issues could not be avoided. However, due to increasing worldwide efforts by many laboratories, a more convincing and clear-cut picture has recently started to emerge. It is the goal of this review to summarize recent reliable data on the cellular and molecular mechanisms of immunosenescence and to try to interpret how basic dysfunctions may eventually lead to disability and disease in the elderly.
Bone Marrow Progenitor Cells
To determine whether abnormalities observed in the aged peripheral immune cell pool are due to deficiencies in progenitor cells or the hematopoietic microenvironment, studies were performed in aged individuals, including centenarians and old mice [4]. These studies indicate that numbers of myeloid and erythroid colonies developing from peripheral blood CD34+ cells of old donors are normal under optimal culture conditions [5], and no major changes in numbers of peripheral leukocytes, platelets, or red cells were observed in the healthy aged [6]. Whether there is a decrease in absolute numbers of bone marrow progenitor cells is not fully understood. However, reimplantation experiments in mice [7] and the poor results of bone marrow transplantation in elderly individuals [8] suggest that the aged bone marrow microenvironment has a significantly reduced ability to support hematopoietic regeneration.
T Lymphocyte Maturation — The Involution of the Thymus
The thymus, the central lymphoid organ, is almost fully developed at birth, but its involution starts soon after puberty and continues throughout life [9]. In the human, thymic tissue is almost completely replaced by fat by the age of 60 [10], and the size of the organ decreases progressively with age [11]. Few intact tissue islands retaining the cortical and medullary architecture seen in the young remain. The phenotypes of all thymic T-cell intermediates are present and there is still ongoing T-cell receptor gene rearrangement [12], but the rate of naive T-cell output of the thymus dramatically declines [13]. Interestingly, experiments in both humans and mice suggest that there are no age-related changes in the total numbers of lymphocytes or in the number of CD4+ or CD8+ T lymphocytes within the peripheral lymphoid pool [14], which may be due to the fact that memory T cells proliferate to compensate for the loss of thymic output, leading to a reduction of the naive T-cell pool [15].
The development of a method for detecting recent thymic emigrants by PCR amplification of the DNA circles formed during T-cell receptor rearrangement (TCR), called T-cell rearrangement exision circles (TRECs), allows for a rigorous analysis of thymic function in old age [16, 17]. This new technology has provided mounting evidence that the age-related changes in the thymus are quantitative rather than
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qualitative, and that even the adult thymus can be reconstituted to some extent [18]. TRECs also rise after bone marrow transplantation in humans, even in recipients over 50 years of age [16, 19]. These recent data indicate that some capacity to produce naive T cells is preserved even in old age. Thus, restoration of thymic function may be a target for immunological intervention in the elderly. Certain types of immune interventions, e.g., affecting the endocrine system, can lead to thymic "rejuvenation," as discussed later in this review.
Naive T Cells
Naive T-cell activation requires T-cell receptor (TCR) stimulation with peptide antigen bound to MHC as well as ligation of T cell coreceptors by costimulatory ligands on the antigen-presenting cells (APCs) [20, 21]. Activation of naive T cells stimulates interleukin (IL)-2 production. IL-2 can upregulate its own specific receptor by induction of aged naive CD4+ T cells produce low levels of IL-2, leading to inefficient generation of effectors. The cells expand poorly, giving rise to few effectors with less activated phenotypes and reduced ability to produce cytokines. The aged cells also respond less vigorously in vivo. Addition of exogenous IL-2 or other y c-receptor signaling cytokines restores expansion. Only effectors generated in the presence of IL-2 are able to produce IL-2 in normal amounts and become polarized to secrete TH-2 cytokines. However, the defect reappears when IL-2-treated cells are reimplanted into irradiated aged or young mice. This suggests that defects in naive CD4+ T cells might be overcome by strategies to induce greater IL-2 availability, leading to more vigorous primary responses. In a more recent study, two further defects in the very early stages of activation induced by peptide and APC complexes were detected in naive CD4 T cells from aged transgenic mice, whose T cells express a TCR specific for a peptide derived from pigeon cytochrome C, at the single-cell level [25]. First, a decrease in the proportion of T cells/APC conjugates that could relocalize signal proteins to the immune synapse was observed. Second, aging diminished the frequency of cytoplasmic NF-AT migration to the T-cell nucleus among cells that could generate immune synapses containing LAT, c-Cbl, or PLC-y. Little is known on the functional characteristics of CD8+ naive T cells in aged mice, and only controversial information is available on the function of naive T cells in the elderly.
Predictions of longevity have been made based on the numbers of naive T cells. Thus, mice characterized by relatively low levels of CD4 and CD8 memory cells and high levels of CD4 naive cells lived longer than conventional controls, indicating that naive T-cell numbers may be used as a biomarker of aging that can predict longevity at middle age [26].
Memory/Effector T Cells
1. Phenotypic Changes
In the almost complete absence of the thymus, the aging immune system is characterized by continuous reactivations, clonal expansions, and elimination of memory/effector T cells of various specificities. This eventually leads to changes in the T-cell repertoire. Various lymphocyte subpopulations change during aging, the most striking change being a shift in the expression of CD45 isoforms from the CD45RACD45RO- to the CD45RA-CD45RO+ subsets in humans [27]. This change occurs within both the CD4 and the CDS pools. The proportion of mouse T cells
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expressing the memory cell marker CD44 also increases with age in the blood, spleen, and peripheral lymph nodes in both CD4+ and CD8+ cells [28]. Studies in aging mice have also documented an increased proportion of T cells expressing glycoprotein P, better known for its role endowing neoplastic cells with multiple drug resistance [29]. The proportion of T cells expressing glycoprotein P also increases with age in humans, although much of the change seems to be accomplished in early adulthood [30]. Interestingly, aged antigen-experienced T lymphocytes lose important costimulatory molecules, such as CD40L [31] and CD28; the loss of CD28 expression has been particularly well documented. Above all, the CD8 subset shows progressively decreasing CD28 expression [32]. CD4+ T cells, almost all of which are CD28+ in young adults, also show an increasing CD28- fraction in the elderly [33]. Telomere shortening in the CD28- cells is more pronounced than in CD28+ cells from the same donor, indicating that the former have undergone more rounds of cell division than the latter [34, 35]. CD28- cells frequently also reaquire a CD45RA+ phenotype [36]. Since these cells also express molecules such as CD 11a and CD95 at high concentrations and have a very polarized cytokine production profile (see below), the phenotype is consistent with a state of terminal effector cell differentiation [37]. Further characteristics, such as loss of growth potential and an increased resistance to apoptosis-inducing stimuli [38], are reminiscent of the well-defined phenotype of senescent fibroblasts or keratinocytes [39]. Terminally differentiated CD8+ T cells also frequently carry the natural killer (NK) cell marker CD56 [40]. Interestingly, the fraction of NK1.1+ T (NKT) cells, a recently described population of T cells that shares some characteristics with NK cells and is restricted by CDld [41], has also been described to be enlarged in the elderly [42].
2. Repertoire
With advancing age, healthy humans frequently demonstrate large clonal expansions of CD8+ T cells in the peripheral blood that persist for long periods of time [43]. These expansions are often remarkable large and may comprise more than 50% of the circulating CD8+ lymphocyte population. CD8+ expansions are essentially undetectable in cord blood and infants and increase in prevalence with age. The etiology of most expansions in healthy individuals is not known, but studies of T cell receptor usage have strongly suggested that these cells arise in response to continued antigenic stimulation [44]. CD4+ T-cell expansions are more rare, but have also been observed in the elderly [45]. The surface phenotype of clonal T-cell expansion in the elderly is also consistent with their prior activation by antigen. They are usually CD45RO+, but sometimes also CD45RA+ (see above), CD28-, CD95+, CDllabright, CD57+, but CD62- [46]. They also lack markers of acute activation, such as HLADR, CD25, and CD69 [47]. Clonal CD28- T cells proliferate poorly in vitro, but have been shown to be autoreactive, which might explain why they are maintained in vivo at a high frequency for long periods of time [44]. Similar clonal expansions have also been detected in aged mice [48].
One can summarize that although absolute and relative numbers of memory T cells increase with aging, their clonal diversity becomes increasingly restricted. Whether the accumulation of large expanded, not fully functioning clones has implications for the development of immunosenescence has not yet been clarified. Recent data from our laboratory indicate that elderly persons who fail to mount a
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humoral response to influenza vaccination have an increased frequency of expanded clones in their CD8 pool that produce large amounts of IFNy, but no other cytokines (unpublished observation). These observations strongly favor the possibility that the presence of expanded clonotypes indeed affects the function of the immune system in old age.
3. Cytokine Production
It is safe to say that cytokine production in old age is one of the most controversial topics in immunological research [49]. Increased, decreased, or unchanged concentrations have been reported for each imaginable cytokine. The reasons for this long-lasting controversy are not entirely clear, but the publication of a relatively large number of well-documented and convincing reports has allowed a more clear-cut picture to recently emerge.
a. Interleukin 2. There is now almost general agreement that total IL-2 production decreases with age [50], for more than one reason. First, and probably most important, the number of naive T cells, which are extremely good IL-2 producers, is greatly diminished [23]. Second, low IL-2 production, low expression of IL-2 receptors, and a poor response to IL-2 have also been observed in memory/effector T cells from older animals and humans [51, 52]. In a model of immunosenescence in which monoclonal T-cell populations can be studied longitudinally throughout their proliferative life span in culture, ability to secrete IL-2 declines as the cultures age. Reduced IL-2 production by memory/ effector T cells in the elderly are presumably due to alterations in signal transduction pathways, but this needs to be further clarified [53].
b. Interferon y. Although many in vitro studies on IFNy production by T cells have shown a decline with age [54], there are now many contradictory indirect indications that interferon-y production, in fact, increases in the elderly. Early studies consistently reported that neopterin, a macrophage product, the production of which can exclusively be triggered by interferon-y, is elevated in old age [55]. In accordance with this result, the production of other interferon-y-inducible mediators, such as tumor necrosis factor (TNF)-a, have also been shown to be increased in many elderly cohorts [56]. There is thus little doubt that aging must be associated with an increase in the whole body load of interferon-y. It is, however, less clear which T-cell types are responsible for this increased production. CD28- terminally differentiated T effector cells may be good candidates, since they produce large amounts of interferon-y and, as mentioned above, increase profoundly with aging. Many laboratories, including our own, have shown a good correlation between the numbers of CD28- cells and interferon-y production [37]. Since CD28- cells may be autoreactive [57], interferon-y production could be continustimulated, which would lead to chronic elevation of basal interferon- y levels in lymphoid or other tissues and might initiate the overall cytokine imbalance and chronic inflammatory state ("inflammage") recently associated with aging [58]. Interferon-y produced by CD28-cells could stimulate monocytes and dendritic cells to produce interleukin-12, which would, in turn, engage interferon-y production by CD28+ T cells and thus induce a vicious circle. On the other hand, interferon-y inhibits the production and some effects of TH2 cytokines. An imbalance between pro- and antiinflammatory cytokines would be the result, which could supposedly support the generation of TH1 rather than
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TH2 cells following priming. Recent data from our laboratory do demonstrate that purified CD4+ T cells from elderly persons, who failed to produce protective antiinfluenza antibodies following immunization, do not produce IL-4 and IL-5 upon in vitro stimulation (unpublished observation). Interferon-y production by NK cells and NKT cells could further contribute to the preponderance of TH1 activity.
c. Interleukin-4, Interleukin-5, and Interleukin-10. It has been long believed that there are age-associated changes in immune responsiveness characterized by a type 2 cytokine phenotype in neonates developing into a predominant type 1 phenotype in adults and reverting to a type 2 phenotype in the elderly [59]. This hypothesis was primarily based on studies in the mouse, but has turned out to be oversimplified and is probably wrong for humans. Previous studies were mostly performed on unfractioned PBMC in which the high proportion of memory cells vs low naive T-cell numbers, a typical feature in the elderly was frequently neglected. Another problem may be that in a subgroup of elderly persons IL-4 seems to be predominantly produced by CD8+ rather than by CD4+ T cells. This surprising finding was recently published [60] and has been confirmed by our laboratory in a study that additionally demonstrated IL-4 production by CD8+ cells as a specific characteristic of elderly persons who are still capable of raising a protective humoral immune response following immunization (Fig. 2). Type 2 cytokine production by CD8 T cells might thus either be a compensatory mechanism that occurs in old age or, alternatively, a genetic feature that allows some circumvention of the functional consequences of immunosenescence. In this context, it is of interest that genetic loci associated with the variation of stem cell cycling activity and longevity have now been mapped. One such locus maps to chromosome 11 in an area containing the IL-3, -4, -5, -13, GM-CSF cytokine gene cluster [61]. IL-1/1L-5 production by CD8 cells from selected elderlies could be under a different regulatory control than in CD4 T cells and could hamper the interpretation of data from un-selected cohorts. Decreased IL-4/IL-5 production by CD4+ T cells in elderly persons who fail to produce specific antibodies after vaccination has already been pointed out above. Further work is needed to clarify signal transduction pathways responsible for the production of IL-4 and IL-5 by the different T-cell subsets in old age. Interleukin-10, an anti-inflammatory cytokine produced by TH2 cell as well as by other cell types, has also been studied in aged humans and mice [62, 63]. Although the literature is, again, relatively controversial, there are strong indications that T cells produce less interleukin-10 in the elderly than in the young [62], which would again support the concept of a cytokine imbalance in favor of TH1 cytokines and a decreased production of Th2 cytokines in the elderly.
4. Helper Function
The significance of T cell help for antibody production by B cells and the effects of aging on this process will be discussed in Section II.G. In the context of memory/effector T cells, it should only be mentioned that the cytokine microenvironment, as well as molecules responsible for cell to cell interactions between T and B cells, are major determinants for intact antibody production in old age. Decreased numbers of CD28+ and CD40L+ T cells, and of a lack of type 2 cytokines, are both likely to endanger normal T-cell/B-cell communication, B-cell growth, differentiation, and antibody production in the elderly.
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5. Cytotoxicity
A decline with age in the in vitro production of antigen-specific cytotoxic T cells. Thus, resting CD8+ cells had a reduced ability to generate clones of cytotoxic effectors when exposed to activating targets plus IL-2 [64, 65]. The question of whether cytotoxic effectors, once generated, show an age-dependent decline in lytic function is controversial, with data in favor as well as against this possibility [66]. The obvious loss of antigen-specific MHC class I-restricted cytotoxicity may be partially counterbalanced by less specific killing mechanisms. Thus, increased numbers and/or increased functional activity of NKT cells, NK cells, and macrophages has been described in old age [42]: These cell types will be referred to in detail later.
6. Proliferation
Once naive T cells have been successfully stimulated, costimulated, and cytokine availability and utility assured, the T-cell response requires clonal expansion. The entry of the cell into the cell cycle is the final consequence of T-cell activation. The expression of protooncogenes such as c-myc and c-myb and the production of IL-2 and its receptor are prerequisites for this process. Decreased expression of these parameters, as frequently observed in old age, may inhibit cell progression from GO to Gl and from Gl to S [67]. T cells capable of entering the cell cycle clonally expand upon antigenic stimulation until a substantial population of one specificity is generated. There is general consensus that the proliferation of T lymphocytes from humans or mice following stimulation with nonspecific stimuli, such as PHA, decreases with aging [68]. This may be due to several defects: Low IL-2 production, low expression of IL-2 receptors, signaling defects, loss of important costimulatory molecules such as CD28, or loss of replicative capacity due to clonal senescence. The latter feature has also been observed in a T-cell long-term culture system [69]. Using this system, some investigators [69] observed lower numbers of population doublings in T cells obtained from old persons. This discrepancy is not surprising, as a residual proliferative capacity may be retained in some T cells until late in life, but may be lost early in others. Consistent with this idea, limiting dilution experiments suggest that murine naive T cells are much more likely than memory T cells to produce IL-2 in culture and more likely to proliferate in response to IL-2 after activation by mitogens or alloantigens. Poor proliferation of CD28 T cells (see above) also suggests that, depending on previous antigenic exposure, certain T-cell populations may proliferate better than others. Loss of the capacity to express telomerase upon activation and short telomeres as a result may be responsible for the loss of replicative capacity in old memory/effector cells [70]. The demonstration of very short telomeres in CD28- T cells supports this theory [34].
F. Cell aging and antibody production
Primary antibody responses in aged humans are often weak and short-lived, and the antibodies produced bind the lower affinity antigens less well than those produced in young adults. Many old individuals also exhibit—mostly benign— monoclonal serum immunoglobulin peaks [71] and there is a strongly increased occurrence of autoantibodies, as discussed below [72]. This leads to a decline in specific antibodies with maintenance of total immunoglobulin levels. Studies in mice have also revealed the absence of a significant increase in the affinity of primary
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antibody responses in old mice (> 22 months). Reduced germinal center reactions are correlated to declining humoral responses in aging in that there is a severe reduction (60-95%) in germinal center reactions in mice of > 22 months of age [73]. The reduction of germinal center reactions is a gradual course in life during which both the number and volume of germinal center diminishes progressively. The lost of robust germinal center responses reduces the conditions for antibody affinity maturation and may also prevent establishment of antibody-forming cell populations in the bone marrow, which act as long-term antibody produces. Parallel to the lost of germinal centers, a reduction in the frequency and size of plasmatic foci in the periarteriolar lymphoid sheath in the spleen is observed [74]. Lymphoid tissue from aged mice also contains atrophic follicular dendritic cells (FDCs), indicating that antigen may be found and trapped less well in the form of unprocessed molecules in old age, which would mean that antigen deposits could last for much shorter periods of time than in the young [73]. This mechanism may be linked to the short-term maintenance of serum antibody titer and the failure to establish fully functioning memory B cells in old age. This is independent of age-related T-cell dysfunction, since FDC develop normally in athymic nude mice [75, 76]. Similar to humans, aged mice also develop clonal B cell expansions, the majority of which derive from the CD5+ subset [72].
Although some of the described phenomena may be the result of intrinsic age-related B-cell defects, the low-level and brief production period of specific antibodies to foreign antigens in the elderly is mainly due to lack of regulatory control of T cells on B cells. In addition to signals mediated by the T-cell antigen receptor and the B-cell receptor, the germinal center reaction and T/B cooperation generally have been found to be dependent on the interaction between costimulatory molecules and their ligands on the T and B cell, respectively as well as on the presence of a certain cytokine microenvironment. It is well established that CD4+ T help is required for germinal center formation and the activation of the IgG somatic hypermutation machinery. Indeed, the rate of IgG hypermutation in germinal center cells is directly proportional to the number of available T helper cells. It has also been demonstrated that T cells may support the expansion of B cells expressing a particular germ-line-encoded VH rearrangement in response to a specific antigen. CD4+ T lymphocytes from aged animals were unable to sustain this preferential expression. Three pairs of cell-to-cell interactions are considered particularly important in this context: CD40 and CD40L, CD80/CD86 and CD28, and 0X40 and 0X40L. While the CD40-CD40L interaction enables B cells to respond to activated T cells, the interaction between CD80/ CD86 and CD28 allows T cells to respond to activated B cells by proliferation and the production of cytokines. 0X40-0X40L interaction plays an important role in B cell activation and plasma cell development [77, 78]. CD40L, CD28, and OX40L have all been demonstrated to be expressed at reduced levels on T cells from aged mice and humans (see also section II.E). Cytokines also play an important role. Although type 1 as well as type 2 cytokines can support antibody production, it is generally accepted that IL-4 (in humans and mice) and IL-5 (in mice) are of particular relevance for enhancing B-cell proliferation of anti-Ig-stimulated B cells and for inducing antibody production. Age-related changes in the production of cytokines have been discussed at length in section II.E, the main message being that
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aging is accompanied by a change in the polarization of the immune response due to a relative overproduction of IFNy accompanied by decreased levels of TH2 cytokines. Macrophages and Dendritic Cells
Recently, there has been major consensus that aging is associated with a chronic activation of innate immunity as the first line of defense [79]. This claim has been made on the basis of many studies demonstrating increased production of cytokines and other nonspecific effector molecules by cells of the innate immune system in the elderly [80]. Thus, increased production of ILla and -P, of TNFa, IL-6, complement, prostaglandin and other monocyte/dendritic cell (DC) products has been observed in aged humans as well as experimental animals. Many reports in which antigen-presenting cells from aged donors have been tested for their ability to support T-cell activation also show no age-related decrease of this specific function [81], although no studies exist thus far in which antigen uptake, processing, and presentation have been analyzed in detail. The reason for the unchanged or even enhanced function of cells of the innate immune system in the elderly is not entirely clear. Most likely, there are several operative stimuli: Excess IFNy production by lymphocytes and NK cells, degenerative processes, clinical and subclinical infection, continuous surface exposure to bacteria or allergens, e.g., in the skin, respiratory tract, or gut. It is also not yet clear how much, and at which anatomic sites, macrophages and DCs contribute to the generation of a proinflammatory status.
In spite of the fact that DCs are known to be the most efficient antigen-presenting cell type to activate T cells and are key modulators of the immune response, very few groups have addressed the topic of DC and aging. DC maturation and aging has been studied in the human system using DC derived from monocytes by in vitro stimulation with IL-4 and GM-CSF [82]. The responsiveness of these cells to maturation-inducing stimuli was tested and found not to be impaired in old age. A recent study additionally demonstrates that, in vitro, the migratory capacity of monocyte-derived DC is not impaired. DC differentiated from monocytes in vitro were also shown to have an unimpaired capacity to stimulate T cells [82, 83]. These results are important because they show that DC can still represent useful tools for immunotherapy in old age, particularly as carriers of tumor vaccines, but there is still a paucity of information about the in vivo situation. Decreased numbers of Langerhans cells (LCs) were described in the epidermis and mucosa from aged animals and humans. The extent of dermal LC reduction was about one third. These results together with those of another study indicating that the capacity of LC to migrate from the skin to the draining lymph node was reduced in aged rodents, may indicate impaired DC migration in vivo. In view of the above-mentioned in vitro results, this may not reflect an intrinsic DC defect, but rather be due to factors such as decreased permeability of tissue barriers. The cytokine microenvironment found in aged peripheral tissues, such as the skin, is also still very poorly defined and may not support optimal DC maturation and migration, but a definitive picture on these important issues has not yet emerged.
In contrast to DC, age-related constitutive defects have been described in macrophages. A recent study indicates that despite an unchanged degree of differentiation, bone-marrow-derived macrophages from aged mice present low levels of MHC class II gene induction by IFNy because of impaired transcription [84].
The consequences of overactivity of the aged innate immune system have recently been a matter of great interest. On one hand, a continuous proinflammatory
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status is now well documented as a factor in the development of age-related disorders not previously associated with immune reactivity, such as atherosclerosis or Alzheimer's disease (see also below). On the other hand, chronic activation of innate immunity is also compatible with extreme longevity in good health, and proinflammatory characteristics have been documented in healthy centenarians, which may at least partially compensate for declining T-cell function [79, 85]. Further work is needed to clarify whether healthy centenarians have a specific genetic background, which protects them from potential detrimental effects of inflammation or whether a certain threshold of inflammation is the prerequisite for the development of diseases.
Natural Killer Cells
NK cells play a critical role in the innate immune response against infections and tumors. In addition to their cytotoxic function, NK cells produce cytokines and chemokines and also express the corresponding receptors. Due to their high IFNy production, they primarily promote THl-mediated immune responses. Age-associated alterations in the number and function of NK cells have been reported by several groups, and there is now general consensus that a progressive increase in the percentage of NK cells with the mature phenotype occurs in elderly donors [86]. The lytic capacity of NK cells considered on a single cell basis, however, is decreased [87], as is the proliferative response of NK cells to IL-2 or other cytokines [88]. In contrast, IL-2-triggered TNFa and perforin production are not impaired [88]. Taken together, the presently available results indicate that age-related functional defects are presumably compensated for by an increased number of mature NK cells; total NK activity thus seems to remain intact even in very old persons.
Activation and signal transduction in immune cells in old age
Very few data are available on the effect of aging on activation signals in APCs or B cells, and these aspects will therefore be excluded from this review. However, substantial amount of work has been performed on the effects of aging on T-cell activation. A reduced calcium influx indicates that early events in T-cell activation are compromised in the elderly [89]. The earliest surface alterations affected by activation such as CD69 and CD71 are also decreased [90], which may, in the first instance, be caused by disturbed signal transduction. Disturbances may be due to alterations in the expression of the TCR or in the signaling cascade through either TCR components or costimulatory molecules. Thus, it has been shown that antibodies against the signal transducing TCR associated CD3£ chain precipitate a series of tyrosine phosphorylated proteins in activated T cells. Although the level of these proteins [91] as well as the association of ZAP-70 with the C chain are retained, their degree of phosphorylation after T-cell activation declines with age in mice and humans [92]. In the same way, the expression level of ZAP-70 is unchanged, but its activity decreases with aging [93] PKC-mediated signaling seems also affected by the aging process. In human T cells, a selective reduction of one isoform of protein kinase C (PKC) has been suggested. In mice, assays for PKC distribution show a decline with age in the proportion of T-cell/APC conjugates that displayed relocalization of PKC0 [95], indicating that a key checkpoint in the activation process may be disturbed. Further data from the literature indicate that T-cell receptor-associated p59fyn enzymatic activity, which is essential for signalling via CD2, but not p56lck activity was reduced in a high proportion of T cells from the elderly compared to the young, although protein levels were the same [94]. The p56lck
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pathway may still be affected by the aging process, as the usual association between CD4 and p56lck may be compromised in T cells from old persons [95]. These data indicate that the very early signal transduction pathways required for T-cell activation are compromised in old age. However, downstream signaling pathways are also affected. Thus, a decreased production of second messengers, such as IP3 and DAG, has been reported [96]. The family of mitogen-activated protein kinases (MAPKs), which are considered essential for normal cell growth and function, also seems to be compromised. In rats, MAPK/RAS activities are decreased in old T cells, and in man, CD3-stimulated T cells from 50% of old subjects showed reductions in MAPK activation [96]. The ERK and JNK kinases have been reported to be diminished in CD3/PMA-stimulated T cells from elderly humans, accompanied by decreased Raf-1 kinase activation. ERK2 activation may represent the rate-limiting step for IL-2 production by old T cells. Although the issue of age-related changes in signal transduction is of paramount importance for the understanding of immunoscenece in general and immunointervention in particular, our knowledge in this area is obviously still far too fragmented to draw clear-cut conclusions with practical relevance.
III. The consequences of immune senescence A. Infectious diseases
The increased frequency and severity of infectious diseases are the most, striking clinical features in the elderly [97]. An example is the high incidence of pneumonia, which is mostly caused either by influenza or by pneumococcal infection. A recent epidemiological study on invasive Streptococcus pneumoniae infections in the United States, for instance, demonstrates that the incidence of disease was highest among children under 2 years of age and adults aged 65 years or older [98]; 28.6% of all patients were at least 65 years old. Influenza is associated with a significantly higher morbidity and mortality in the elderly [99]. Each year, tens of thousands of deaths are attributed to influenza and related complications, such as pneumonia, and 80% of influenza deaths occur in individuals over 65 years of age. Other infections that frequently occur in the elderly are urinary tract and skin infections and an increase in hospital-acquired and nursing home infections. Impairments in primary host defenses also contribute to the increased rates of infections, such as reduced cough reflex leading to aspiration pneumonia, urinary and fecal incontinence predisposing to urinary tract infections, and immobility predisposing to wound infections. Old individuals may also fail to respond normally to therapy for infection and may present with infections secondary to unusual organisms (opportunistic infections), recurrent infections with the same pathogen or reactivation of quiescent diseases, such as those caused by M. tuberculosis and herpes zoster virus. The latter disorder is caused by Varicella zoster virus and is increasingly prevalent with advancing age, as are its severity and complications.
A relatively new and exciting facet of infectious disease-associated age-related complications concerns atherosclerosis, one of the main killers in the developed world. It has long been known that immunologic/inflammatory processes take place during the development of atherosclerosis, but it was not clear whether these events were of a primary or secondary nature. During the past decade, we have developed a new "autoimmune" hypothesis of atherogenesis that describes a common denominator for all types of infections that have been incriminated as possible initiating or perpetuating factors in atherosclerosis [100]. We have shown that humoral antibodies and T cells reactive with the stress protein heat shock protein 60
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(HSP 60) seem to be the effector mechanisms that lead to the damage of stressed arterial endothelial cells [101] and subsequent mononuclear cell infiltration of the intima and, when classic atherosclerosis risk factors (such as high serum cholesterol levels, etc.) persist, progress into fatty streaks and finally severe lesions, i.e., atherosclerotic plaques.
HSPs are phylogenetically highly conserved constituents of prokaryontic and eukaryontic cells classified into various families according to their molecular weight [102]. Here, the 60-kDa HSP family is of special interest, members of which constitute a considerable number of the total proteins of viral envelopes, bacteria, and parasites. Among other physiological properties, HSP 60 act as chaperones, i.e., are expressed after mild stress, associate with other proteins of the organism and protect them from denaturation. Similar to the situation in microbial organisms, stressed human cells also express PISP 60 that exert a chaperoning function. Classical risk factors for atherosclerosis (i.e., high blood pressure, smoking, overweight, high blood cholesterol levels, diabetes, etc.) lead to the expression of HSP 60 by arterial endothelial cells, especially at those areas of the vascular tree that are subjected to major hemodynamic (turbulent) stress, notorious predilection sites for the later development of atherosclerosis. Due to the life-long exposure of arterial endothelial cells to higher blood pressure as compared to venous endothelial cells, the former show a lower threshold for HSP 60 expression after being subjected to various stress factors [103].
We have shown that atherosclerosis may be the price exacted for our protective immune reactivity against microbial HSP 60 by a cross-reactivity with autologous HSP 60 expressed on the surface of arterial endothelial cells when these are stressed by atherosclerosis risk factors. A second possibility, of course, is the emergence of bona fide autoimmune reactions as a response to biochemically altered autologous HSP 60 released in the case of various types of cellular damage or protein modification after appearance in the circulation [104], HSP 60 that cross-reacts with human HSP 60 [105, 106].
The low protective effect of vaccination in the elderly
Infectious diseases in the elderly might be principally prevented by vaccination, but the protective effect of vaccination is poor in old age [107]. Decreased antibody production and shortened duration of humoral protective immunity following immunizations are characteristic in persons of more than 60 years of age [108]. At best, incomplete protection of elderly adults is afforded by the present influenza and pneumococcal vaccines [109], and vaccines known to achieve satisfactory immunization results in children and younger adults also leave much to be desired in the elderly [110]. A cohort of 300 elderly (> 60 years) and 300 young (< 35 years) persons was recently analyzed in laboratory for the presence of specific antibodies against tetanus, diphtheria, tick-borne encephalitis, and influenza.
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