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Does the Immune System Grow Old Gracefully?

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Does the Immune System Grow Old Gracefully? Immunology Does the immune system grow old gracefully? Donald B. Palmer ‘You don’t stop laughing when you grow old, you grow old when you stop laughing’. and Tamar Freiberger George Bernard Shaw Downloaded from http://portlandpress.com/biochemist/article-pdf/41/1/26/851497/bio041010026.pdf by guest on 27 September 2021 (Royal Veterinary College, University of London, UK) The immune system consists of an array of cells and Making T cells can be exhausting soluble factors that are designed to protect the host from pathogens and infectious diseases, and therefore T cells represent a key component of the immune system; represents a vital entity for an organism’s survival. they are able to directly remove pathogens as well as Moreover, with increasing age, the immune system coordinate other elements of the immune system to elicit undergoes dramatic changes resulting in a decline in their function. A large number of studies have suggested immune function, which is seen in humans as well as in that a progressive decline in T cell function is one of the many other species. Such changes, collectively termed major factors that contributes to the clinical features of immunosenescence, often lead to increased susceptibility immunosenescence. T cells are derived from haematopietic and severity of infections, cancers and autoimmune stem cells (HSCs), however for HSCs to become T cells diseases, together with the reduced ability to respond they are required to enter the thymus (a primary lymphoid to vaccination, which is often seen in older individuals. organ) and in the presence of appropriate signals, provided Given the direct correlation between immune function by the thymic environment, differentiate into T cells. and health, the increased morbidity and mortality seen Moreover, the thymus is solely responsible for producing in older individuals following infection are due, in large T cells, such that failure to generate the thymus leads to part, to the age-associated changes in the immune system. the absence of T cells in the peripheral circulation (i.e., the This is of great concern since, according to the Office of entire vascular system). National Statistics, the population of individuals over Involution is a general term for the shrinkage of the age of 65 in the UK is steadily increasing, standing an organ in old age, or due to inactivity (e.g., post-birth at 18.2% in mid-2017 and estimated to rise to 20.7% by reduction in the size of the uterus). Age-associated thymic 2027 and 24% by 2037 (Figure 1); a trend that is also seen involution (Figure 2) is one of the most recognizable globally. Although this area of research is relatively new in features of the aging immune system. This regression of the comparison to other fields of immunology, investigations thymus is associated with a reduction in tissue mass, loss of have identified several differences between the young and tissue structure and a decline in the number of thymocytes aged immune system which has helped shed light on the (T cell precursors). Ultimately, this leads to a reduced Figure 1. Graph showing possible mechanisms associated with immunosenescence. production of new (naive) T cells, the consequence of the proportion of the UK which has major ramifications on functional immunity. population aged 65 years Why the thymus involutes with age is still unclear. One and over, which is steadily suggestion is that thymocyte development is highly energy rising and predicted to be demanding and once the T cell pool is established (as T one in every four people by cells are long-lived), the thymus regresses, so that energy 2037. Graph taken from the can be redirected to other cellular systems. Nevertheless, Office of National Statistics: this process occurs in all species that possess a thymus, https://www.ons.gov.uk/ which not only indicates that age-associated involution peoplepopulationand is an evolutionary-conserved event, but also makes it a community/population suitable biomarker of aging. The start of thymic involution andmigration/ is believed to occur during adolescence; however, there is populationestimates/ significant evidence to suggest it may occur earlier in life. articles/overviewofthe Furthermore, thymic activity does not decline at a steady ukpopulation/ rate, but instead appears to be phasic (Figure 2). The onset november2018 of thymic involution appears to be relative to the lifespan of 26 February 2019 © The Authors. Published by Portland Press Limited under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) Immunology Downloaded from http://portlandpress.com/biochemist/article-pdf/41/1/26/851497/bio041010026.pdf by guest on 27 September 2021 Figure 2. Age-associated thymic involution and how it impacts the peripheral T cell pool. a) A schematic diagram showing the rate of age-associated thymic involution (as measured by thymic size) recorded in a number of animals. The regression of thymic size is not linear, but phasic with the greatest loss occurring early in life followed by a steady decline. b) The thymus structurally consists of a cortex and a medulla, represented as I and X respectively. In young individuals, the cortex and medulla are distinct, the thymus has a high output of naive T cells and the T cell repertoire is diverse in the periphery. However, in the aged, the thymus is reduced in size and disorganized, and T cell output is reduced (as illustrated by the arrow). Furthermore, cells produced from the aged thymus may not be as robust as those from a young thymus. The number of peripheral T cells does not change with age, so the vacancy created by the reduction of naive T cells is filled by existing memory cells. Consequently, the peripheral pool in the aged is less diverse and contains cells with a reduced proliferative capacity. the host, since studies from our laboratory on dog breeds can indeed be detrimental to host survival. For instance, with varying lifespans, showed that the thymus began to having a reduced diversity to recognize foreign antigens regress at an earlier age in short-lived breeds compared is likely to leave older individuals more susceptible to with long-lived breeds. new pathogens. Furthermore, the inability to proliferate Although the exact causes of thymic involution will cause inefficient T cell responses to antigens as well are still unclear, evidence suggests the involvement of as reducing their capacity to provide help for B cells, both cell-intrinsic abnormalities and defects from the which is one of the reasons why vaccine efficacy is often extrinsic environment. For example, early thymocyte poor in older populations. progenitors from an aged murine thymus have a reduced The age-associated alteration of the peripheral T cell capacity to generate into T cells. This might be due to pool also includes the presence of T cells that lack the perturbations acquired from aged HSC since these co-stimulatory marker CD28. This marker is expressed cells have a reduced potential to differentiate into the in all T cells at birth and is essential for T cell activation lymphoid lineage. As previously mentioned, the thymic by promoting division, survival and differentiation. environment is essential for T cell differentiation and However, with age there is an accumulation of T its components are also likely to contribute to thymic cells that have lost this molecule and are thus ‘CD28 involution. In particular, thymic epithelial cells from negative’ (CD28-). This occurs more rapidly among aged mice have been shown to be defective in supporting CD8+ (cytotoxic) T cells compared with CD4+ (helper) thymocyte development. T cells. These CD28- T cells exhibit similar features to replicative senescent cells as they have reduced Knock-on effects of thymic involution proliferative capacity, telomere erosion and secrete pro-inflammatory cytokines. The latter characteristic The consequence of a decline in naive T cell output from resembles the senescence-associated secretory the aging thymus has a major impact on the peripheral phenotype (SASP) (the SASP refers to senescent cells T cell pool. This includes a reduction of diversity due to that secrete a variety of pro-inflammatory cytokines and the steady accumulation of T cells that exhibit a memory contribute to tissue dysfunction). Furthermore, CD28- phenotype (Figure 2). In addition, with increasing age, T T cells appear to have a negative effect on the immune cells exhibit: (1) a reduced proliferative capacity, (2) an response and may therefore play a part in the decline of inability to provide support for other immune cells and functional immunity in the aged. Interestingly, both the (3) altered production of cytokines. Such modifications accumulation of CD28- T cells and the gradual increase February 2019 © The Authors. Published by Portland Press Limited under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) 27 Immunology of a memory T cell phenotype within the aged immune fewer recognition receptors, such as toll-like receptors. system appear to be driven in part by persistent viral Other innate cells, natural killer (NK) cells, show an infections. For instance, several studies have observed age-related increase in frequency, however they exhibit high proportions of cytomegalovirus (CMV)-specific reduced cytotoxicity. As NK cells play a key role in CD8+ T cell clones in the blood of older individuals, viral immunity and the removal of cancer cells, their which demonstrates a positive correlation between decline is likely to contribute towards the clinical signs CMV and the presence of senescent T cells. It is believed of immunosenescence. that this virus has the ability to induce premature aging B cell function is also reduced with age, in part due and exhaustion of T cells and is viewed as a risk factor for to a decline in T cell help, but also their development immune-related morbidity and mortality.
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