The state of the aged adaptive immune system can be assessed in a practical way in animal studies, such as via exposure to influenza or other well-calibrated infectious disease. This assessment is also carried out on the human population as a whole in every influenza season, but for individual humans one wants a metric that is a little less do or die. The adaptive immune system is made up of many different subtypes of B cell and T cell, each serving a different purpose. While the overall population of T cells remains fairly consistent with age, the size of different T cell subtype populations changes in characteristic ways. Based on this, metrics of immune function can be created.
T cells are characterized by the surface markers they expose, and the number of cells with a given marker or combination of markers can be counted in a flow cytometry machine, given a blood sample to work with. There are a very large number of these markers, and countless combinations, but some are established to be much more important than others. CD4 is a marker of T helper cells, which serve a variety of coordinating roles in the immune response, for example, while CD8 is a marker of cytotoxic T cells, responsible for killing errant cells and pathogens. This is an overly simplistic description of a very complex array of cell states and behaviors, but it is useful, as demonstrated by the fact that the CD4/CD8 ratio of T cells in a blood sample does, on balance, reflect the state of the immune system as a whole. A low CD4/CD8 ratio correlates with a greater degree of frailty and comorbidity in older people.
The CD4/CD8 T-cell ratio is emerging as a relevant marker of evolution for different pathologies and therapies, including cardiovascular diseases. Immune alterations related to cellular immunosenescence, together with persistent inflammation, are known to be involved in the process of deleterious aging, which underlies the failure to maintain global health status during aging. The CD4/CD8 ratio might be related to cellular immunosenescence, and potential factors affecting the CD4/CD8 ratio in older people have been extensively studied.
Cytomegalovirus infection has been widely reported as the main cause of CD8 T-cell oligoclonal expansion. Additionally, free radicals, which accumulate during aging, may have an impact because subjects with an inverted CD4/CD8 ratio exhibit reduced levels of antioxidant defenses and higher oxidative stress. Hence, factors associated with cumulative cellular senescence and oxidative stress appear to trigger a reduction in the CD4/CD8 ratio; however, the immunological features beyond CD4/CD8 T-cell ratio values require further exploration.
It is reasonable that CD4/CD8 T-cell ratio values, particularly in older people, might reflect different degrees of immune capabilities both for responding to antigens and for preserving health status in this population. Although thymic output is the main regulator of T-cell homeostasis, whether it relates to the CD4/CD8 T-cell ratio in older individuals has not yet been explored. Notably, the thymus undergoes progressive atrophy throughout life, reducing its activity by approximately 3% per year until middle age, when it slows down to less than 1% per year.
Nevertheless, the thymus remains active in adults, contributing to the renewal of the pool of naïve T-cells, even though thymic function is highly variable in older people. In fact, intrathymic CD4+CD8+ double-positive T cells obtained from thymic biopsies correlate not only with age (negative) but also with the frequency of naïve T cells (positive). Interestingly, a relationship between thymic function and the CD4/CD8 T-cell ratio exists in HIV infection, which is a different scenario but shares several immunosenescence traits with aging. On the other hand, it is also reasonable that CD4/CD8 T-cell ratio values might correlate with different inflammatory profiles. To better understand the biological meaning of the CD4/CD8 ratio in the elderly, we explored the phenotypic profiles of both CD4 and CD8 T-cells, as well as the thymic output and several inflammation-related parameters, in a population of older subjects classified according to CD4/CD8 ratio value.
The lower CD4/CD8 ratio group showed a lower thymic output and frequency of naïve T-cells, concomitant with increased mature T-cells. In these subjects, the CD4 T-cell subset was enriched in CD95+ but depleted of CD98+ cells. The regulatory T-cell (Treg) compartment was enriched in CTLA-4+ cells. The CD8 T-cell pool exhibited increased frequencies of CD95+ cells but decreased frequencies of integrin-β7+ cells. Interestingly, in the intermediate CD4/CD8 ratio group, the CD4 pool showed greater differences than the CD8 pool, mostly for cellular senescence.
Regarding inflammation, only high sensitivity CRP was elevated in the lower CD4/CD8 ratio group; however, negative correlations between the CD4/CD8 ratio and β2-microglobulin and soluble CD163 were detected. These subjects displayed trends of more comorbidities and less independence in daily activities. Altogether, our data reveal that different thymic output and immune profiles for T-cells across CD4/CD8 ratio values that can define immune capabilities, affecting health status in older individuals. Thus, the CD4/CD8 ratio may be used as an integrative marker of biological age.