The Immune System in the Elderly: A Fair Fight Against Diseases?

Anis Larbi; Paulina Rymkiewicz; Anusha Vasudev; Ivy Low; Nurhidaya Binte Shadan; Seri Mustafah; Shamini Ayyadhury; Tamas Fulop


Aging Health. 2013;9(1):35-47. 

In This Article

T and B Cells in aging

The number and frequency of T cells are variably mentioned to decrease with age; however, no clear consensus exists. Thymopoiesis is reduced in aging leading to reduced frequency and number of naive T cells (CCR7+CD45RA+ cells). This also translates to increasing frequency and number of memory cells. There are several memory subsets in the CD4 and CD8 compartments. Based on surface markers used to distinguish these, there are central memory (CCR7+CD45RACD45RO+CD28+CD27+), effector memory (CCR7CD45RACD45RO+CD28+/-CD27+/-) and late differentiated (CCR7CD45RA+CD45ROlowCD28CD27) cells. The frequency of CD28 T cells, which is often associated to aging of the immune system, encompass both the effector memory and T-effector memory re-expressing CD45RA (TEMRA) cells and discrepancies exists between CD4 and CD8 T cells.[15] These memory cells tend to expand when they recognize antigens from persistent infectious agents such as cytomegalovirus (CMV). In the elderly, up to a quarter of all CD8+ T cells may be specific for just one CMV antigen, suggesting a profound impact on T-cell repertoire diversity (Figure 1). However, this effect is not restricted to elderly individuals, as shown by studies in African infants aged 2 years and younger.[16] Seropositivity to CMV infection in these infants led to a tremendous change in CD8+ T-cell profile, while this was not observed in CMV seronegative infants. This suggests that where CMV is highly prevalent, the changes induced at the immunological level may happen earlier. Some markers are associated with lack of functionality of T cells. CD57 and KLRG-1 are associated with lack of proliferative response, and as such, are considered markers of replicative senescence. These cells lack expression of costimulatory molecules such as CD28 and CD27. A majority of the expanded cells are expressing CD57, KLRG-1 or both. This suggests that antigen-specific T-cell expansion is leading to an increased proportion of replicative senescent cells. This can be beneficial for the control of CMV infection, but is participating in the filling of the immunological space that impacts on the repertoire diversity. Recent longitudinal studies have associated CMV infection with mortality associated with a high proinflammatory profile (C-reactive protein [CRP]high, IL-6high, TNF-α). The immunological history (the number and frequence of antigens seen during life) is a strong determinant of immunological aging. Immunological aging is defined by the extent of senescence detected at the immunological level. To date, this mostly involves T cells, but B cells can also be identified as senescent. A reduction in production and function of B cells lead to increased susceptibility to diseases, reduced responses to vaccination and increased cancer incidence in aged populations.[17] Both the number and the function of B cells are known to decline in an age-dependent manner.[18] Specifically, aged mouse B cells exhibit increased production of low-affinity antibodies due to decreased isotype switching.[19] The decline in humoral responses in elderly people is attributed to changes in the composition of the cells comprising the B cell repertoire. Fewer naive B cells are found in elderly populations compared with the numbers found in young adults. Moreover, these cells are replaced in the cell pool by antigen-experienced memory cells, some of which are 'exhausted' B cells (CD19+IgDCD27). There is also a decrease in overall antibody affinity found in elderly populations due to a general isotype switching from IgG to IgM antibodies.[17,19] Reductions in B-cell lymphopoiesis in old age could contribute to reduce tumor immunosurveillance. In humans, the age-associated decline in B-cell lymphopoiesis is less drastic compared with mice, and it appears that loss of B-cell diversity is strongly associated with poor health rather than age.[20] The reduction in B-cell lymphopoiesis is compensated by a longer lifespan of maturated B cells in aged mice. It has been estimated that only 10% of B-cell lymphopoiesis is maintained in old compared with young mice, and that a complex system of adaptation exists to keep a certain level of B-cell functionality and protection in aged mice.[21] It is less clear in humans if and how this adaptation happens, and comparisons between the two models may prove difficult as diseases in mice and humans are different and cannot be assessed in similar details. It can be hypothesized that immune compartments are not affected similarly in humans compared with mice, based on the fact that the differential regulation of the immune response and the encounter of antigens during life may lead to different outcomes in terms of memory generation and susceptibility to senescence.