Immunosenescence in vertebrates and invertebrates
© Müller et al.; licensee BioMed Central Ltd. 2013
Received: 28 November 2012
Accepted: 14 March 2013
Published: 2 April 2013
There is an established consensus that it is primarily the adaptive arm of immunity, and the T cell subset in particular, that is most susceptible to the deleterious changes with age known as “immunosenescence”. Can we garner any clues as to why this might be by considering comparative immunology and the evolutionary emergence of adaptive and innate immunity? The immune system is assumed to have evolved to protect the organism against pathogens, but the way in which this is accomplished is different in the innate-vs-adaptive arms, and it is unclear why the latter is necessary. Are there special characteristics of adaptive immunity which might make the system more susceptible to age-associated dysfunction? Given recent accumulating findings that actually there are age-associated changes to innate immunity and that these are broadly similar in vertebrates and invertebrates, we suggest here that it is the special property of memory in the adaptive immune system which results in the accumulation of cells with a restricted receptor repertoire, dependent on the immunological history of the individual’s exposures to pathogens over the lifetime, and which is commonly taken as a hallmark of “immunosenescence”. However, we further hypothesize that this immunological remodelling per se does not necessarily convey a disadvantage to the individual (ie. is not necessarily “senescence” if it is not deleterious). Indeed, under certain circumstances, or potentially even as a rule, this adaptation to the individual host environment may confer an actual survival advantage.
Here, we will briefly review some of what is known about age-related changes to innate immunity in experimental models and in humans, and to adaptive immunity in higher animals, most particularly humans. It may be instructive to consider examples of invertebrates, which possess solely humoural innate defences (selecting C. elegans as the best, albeit still very superficially, investigated), then invertebrates with both cellular and humoural innate immunity (mostly Drosophila) and finally vertebrates possessing both innate and adaptive immunity (focussing on humans, except where reference must be made to another well-studied species: the mouse).
Despite the relative wealth of knowledge on insect immunity, surprisingly little is known about age-related changes to immune competence. Levels of anti-microbial peptides increase with age, and this has been associated with a decrease in fecundity  but not lifespan . However, linking ageing with oxidative stress, gene transcription studies suggested that similar patterns of gene expression changes were induced in young flies exposed to oxidative stress as in old flies not otherwise stressed ; many of the genes upregulated with age were related to immune function . More recently, infection models have suggested that old flies have more trouble clearing bacterial infections due to altered expression of genes involved in energy metabolism and insulin signalling . One mechanism for this may be the decreased phagocytic activity of haemocytes in older flies . However, there appears to be a great deal of heterogeneity between different populations of Drosophila, with age affecting immunity negatively but also positively in some lines . Thus, much remains to be learned in this relatively unexplored area of comparative immunogerontology.
Vertebrates are unique in that in addition to retention of innate immunity of the types found in invertebrates, they also possess a sophisticated cellular and humoural immune system (Figure 2) exploiting clonotypic antigen receptors and imbued with memory (so-called “adaptive immunity”). They also possess other specialized cells that are part of the innate system but act as a bridge to the adaptive system and are not present in invertebrates. Thus, these cells (especially the antigen-presenting cells, DC, or NK cells) could also be responsible for age-associated decreased immunity in vertebrates; however, while changes are recorded, they do not seem as extravagant as those recorded for T and B cells (see following sections). Most information that we have on the ageing immune system in vertebrates derives from experimental studies in mice, with limited data also available in other rodents, cats, dogs, horses and non-human primates, in general consistent with the data from mice; extensive data are also available from observational studies in humans. Here, we will focus on the latter, but refer to rodent studies where human data are lacking or insufficient. Because, despite many similarities, mouse and human immunity can be different, we will indicate when referring to mouse data instead of human.
Age associated differences in innate immunity in vertebrates
Natural killer cells
Age-associated differences in adaptive immunity
For the development of functional immunity, pathogens must be detected and responded to appropriately. For this purpose, surface receptors must bind specific ligand and trigger cell activation only when challenged with pathogen-derived molecules. As discussed above, the cells of the innate immune system achieve this by means of germline-encoded receptors recognizing a limited variety of targets present on micro-organisms but not found in the host (Figure 1), whereas cells of the adaptive immune system employ highly polymorphic receptors created by the random genetic recombination of diverse elements to assemble recognition units of enormous diversity. Antigens derived from pathogens must be taken up and processed by APC (most usually DCs as mentioned above) and presented on the cell surface to T cells (Figures 2, 7 and 8). It is therefore of paramount importance that both partners in this interaction are functioning in an optimal manner, both the T cells derived from potentially age-compromized HSCs and processed through a markedly age-affected thymus before being released to the periphery (Figure 9).
Immune cell function
The number and relative proportions of cell surface receptors mediating co-stimulation are variable according to differentiation stage of the T cell such that they also change with age, disease and functional status. Indeed, decreased or absent expression of one of the well-studied costimulatory receptors, CD28, was proposed many years ago as a biomarker for immunosenescence . This is consistent with findings that late-differentiated CD8+CD28– T cells tend to accumulate particularly in the elderly in the immune risk profile group, and because CD28 expression is lost on in vitro culture prior to CD8 T cell replicative senescence. However, regulation of CD28 expression is likely to be part of the T cell differentiation program, rather than necessarily a sign of senescence. Moreover, CD28 may be up- or downregulated by cytokines such as IL-12 and TNF, respectively, independently of senescence. Altered signal transduction events in T cells have been much studied, but it remains unclear to what extent they are a result of altered proportions of the expressed positive and negative co-stimulatory receptors, like CD28 and its related negative signalling receptor CD152 (CTLA-4), or whether altered signal transduction pathways for each receptor, or both, are most important in determining the final outcome (ie. activation, anergy or apoptosis). In vitro studies on clonal cultured T cell populations may allow us to distinguish between changes caused by altered proportions of cell subsets and changes within the same clones at different times, eg. in the expression of the receptors alluded to above. Even for TCR signalling itself, differences between young and old donors´ naïve and memory T cells, or between CD4+ and CD8+ T cells, are not yet sufficiently well delineated.
B cell function In addition to the commonly decreased numbers of peripheral B cells in the elderly, especially those in the IRP group, age-associated changes to B cells and their subsets are also observed. These are less-well studied than in T cells, but like T cells, memory B cells do most likely accumulate with age, although data from different studies are discordant . One reason for discrepancies might reside in the application of the markers identifying memory cells; as with T cells, it is differentiation states and not really subsets that are being measured . At the functional level, age-associated alterations in immunoglobulin generation during immune responses have been reported, both via Ig class switching and somatic hypermutation . This could be one mechanism accounting for the decline of the quality of humoral responses in the elderly. Further data on B cell alterations are needed, particularly since decreased absolute numbers of B cells may be associated with earlier mortality in longitudinal studies of the very elderly.
Immune cell turnover As discussed above, thymic output of naïve T cells is greatly decreased in older people, and often assumed to be negligible; nonetheless, in healthy elderly donors, peripheral T cell homeostasis is generally well maintained so that numbers of circulating T cells remain constant. How can this be accomplished? The answer is not likely to be extra-thymic generation of naïve T cells, but rather, the peripheral expansion of pre-existing T cells. Experiments to assess T cell dynamics are difficult in humans, but one pioneering approach exploits the incorporation of deuterated glucose into dividing lymphocytes (T cells, B cells and NK cells) to track their turnover. In naïve, memory and regulatory T-cells, glucose uptake and its subsequent loss occurs rapidly. Interestingly, it is the regulatory T cells that appear to proliferate the most rapidly . One major important age-associated difference is that CD8+ memory cells in the elderly cycle considerably more slowly than any other subset, but this is not the case in young donors. This finding is consistent with the noted accumulation of CD8 memory cells in old people, since they may not reach a state of replicative senescence so quickly and are apoptosis-resistant , whereas the opposite is true of CD4+ T cells. B cells also showed some differences, but in this case it was the memory B cells that turned over more rapidly than the naïve cells. For NK cells, production and proliferation rates were lower in the elderly than in the young, which may also be relevant to the finding mentioned above that NK status is important for healthy ageing and infection resistance .
Because of the rapid T-cell turnover revealed by these studies, and given the Hayflick limit to the number of cell divisions normal somatic cells can undertake before senescence, it would be predicted that the proliferative capacity of the individual T cell clones constituting the response would eventually become exhausted . Especially CD8 cells at this late stage express a highly differentiated phenotype (CD27 and CD28-negative, short telomeres, lack of telomerase and expression of negative signalling receptors like PD-1, CD57 and KLRG-1) . In analogy with so-called replicatively senescent fibroblasts with altered cytokine secretion patterns, late-stage memory T-cells may also acquire new functions such as suppressive activity as previously demonstrated in vitro a decade earlier . The mechanisms by which such “exhausted” cells suppress may include competition for cytokines or antigen on the DC surface, altered cytokine secretion patterns, or acquisition of cytotoxicity. At this stage, chronic stimulation by the original antigen itself is probably no longer necessary to keep the cells constantly turning over; hence memory T cells can persist for a lifetime, long after antigen exposure, even in the absence of persistent infection or periodic re-infection. Turnover may be supported by cytokines released by other cells reacting to completely different antigens (the so-called “bystander” effect). Thus, T-cell clonal exhaustion could be said to be an intrinsic characteristic of adaptive immunity, continuing even in the absence of specific chronic infection. However, in natural human populations, and even in sanitized Western societies, certain chronic infections or some other infections are always likely to be present. In every country studied so far, commonly persistent “asymptomatic” viruses and other pathogens which co-exist usually in a peaceful (perhaps even mutually beneficial?) association with the host are found. One of these, the beta-herpesvirus HHV5 (Cytomegalovirus, CMV), stands out from the rest as a common driving force for the observed age-associated immune alterations. Of course, this does not exclude the possibility that in different environments where CMV is less prevalent (should there be any, since CMV appears endemic in humans, and not being infected with it may actually be an artefact of civilisation), or for other reasons, other pathogens may play a similar role. Some similar phenomena linked to T cell clonal exhaustion, senescence and suppression may also occur in many disease states, such as in HIV infection, cancer and autoimmunity, in all of which different sources of antigen could act as a chronic immune stimulant. Thus, we would argue that age itself may not influence peripheral senescence events directly, but acts indirectly via the impact of differential pathogen loads and different durations of infection to exhaust the mature immune system . In the absence of large-scale production of naïve T cells as a consequence of thymic involution and the limited capacity of the peripheral “immunological space” to absorb the accumulating memory cells, adaptive immunity becomes progressively compromised.
Studying immunity in model organisms can be informative for determining the effects of age and might point the way to seeking previously unsuspected age-associated alterations in certain components of the human immune system otherwise obscured by the complexity of the whole. However, this is manifestly true only for components of innate immunity. The greater susceptibility to immunosenescence of the adaptive arm of immunity relative to the innate arm is suggested to be due to the necessity of maintaining clonal expansions of memory cells unable to self-renew in the way that innate immune cells can. This is the price paid for a much larger receptor repertoire of adaptive compared to innate immune cells, which in turn may be required to maintain homeostasis of the gut microbiota, keeping pathogens at bay while not reacting to the majority of symbionts.
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