T Cells

T cells are a type of lymphocytes generated in the thymus. Based on their co-receptor molecules, they can be distinguished in CD4+ and CD8+ cells.
Among CD4+ lymphocytes are T helper cells, which are the immune cells leading the fight against infections. CD4+ cells are involved in the identification and destruction of bacteria, fungi, and viruses. By releasing cytokines, they activate neighboring cells and by chemokine secretion, they recruit new immune cells.
Among CD8+ lymphocytes are cytotoxic T cells. These lymphocytes identify and kill cells infected by viruses and cancer cells by delivering cytotoxic granules into them. Just as CD4+ cells, CD8+ cells also produce cytokines. Typically, a T cell response peaks in 7-15 days, after which the vast majority of antigen-specific T cells dies off, leaving a pool of memory cells. Both CD4+ and CD8+ lymphocytes can leave centralmemory and effector-memory cells. The former can extensively proliferate after antigen reencounter, while the latter are characterized by limited proliferative potential but possess a rapid effector, cytolytic, function. Effector-memory cells are thus considered first responders to peripheral reinfection controlling the initial re-exposure to a pathogen, allowing central-memory cells the time to proliferate and create new effectors. Memory cells can survive for decades, with a half-life of 8-15 years. That is why overexuberant exposure to antigens can compromise immune memory: overdifferentiation of T cells can limit the immunological space available for new memory cells. In fact, the immune system works to maintain the number of peripheral T cells at almost constant levels. Therefore, the increase in differentiated T cells reduces the space for new T cells.
For example, chronic viral infections lead to continuous stimulation of T cells, increasing the risk of clonal exhaustion and overdifferentiation of all the viralspecific T cells into effectors. In general, both inflammatory and immuno-modulating signals are required for proper effector and memory function. However, the overcommitment to one or the other can lead to dysfunctional immune responses. Unfortunately, the increase in life expectancy does not always coincide with the increase in healthy, freeof- disease, years to be lived. For example, the elderly are characterized by a decrease in their ability to resist new infections. Changes in the T cell population are partially responsible for phenomena like this. In the elderly, reduction in total T cell number has been reported, and the decreased ability to resist new infections is associated with the reduction of naïve T cells – that is, newly produced, resting cells that can be activated by an interaction with an antigen.

This phenomenon was suggested to contribute to the differences in longevity between sexes. CD4+/CD8+ inversion might represent a step toward a progressive CD4+ lymphocytopenia, a rare condition in aged people. In this case, factors affecting the CD4+ population could be the cause of the inversion. However, aging-associated CD8+ cell changes are more important. In particular, healthy elderly clonal expansion has been reported and has been associated with a CD28- subpopulation, lacking in proliferative responses to T cell receptor stimuli. Moreover, the CD4+/CD8+ balance may be altered by some conditions, particularly viral infections. Cytomegalovirus (CMV) positivity, a leading cause of immune system senescence, is closely related to the inversion of the CD4+/CD8+ ratio. CMV infection, that persists lifelong after the first exposure, chronically stimulates CD8+ cells, which expand and demonstrate a memory-effector phenotype. CD4+ cells decrease in a compensatory way. In the IRP, marked seropositivity for cytomegalovirus is associated with reversal of CD4+/CD8+ ratio, the increase in CD8+CD28- memory-effector cells and in proinflammatory cytokines such as IL-6, and the reduction of B cells (CD19+). This condition is predictive of the development of cognitive deficits, and of mortality rate over the next 4 years in 58% of cases.
Even if a significant number of adults are positive for CMV, only a minor part of them is aware of its seropositivity; as a consequence, they are unaware of their possibly compromised immune defenses. Other conditions associated with CD4+/ CD8+ inversion are transplantation, hemophilia treatment, acute illness, and malnutrition. In many cases, T cell subpopulations are only temporarily affected; however, CD4+/CD8+ ratio can remain altered in the long term. In general, both microbial agents and environmental stressors can initiate T cell changes; an immune system lacking the required resilience might foster a progressive change in the CD4+/CD8+ ratio toward unhealthy values. In the elderly, CD4+/CD8+ ratio values greater than 2 have been reported. It must be noted that, besides strong immunity, such values can be associated with specific pathologies, such as infections and blood cancers. Moreover, as opposed to the mean, the median elderly CD4+/CD8+ ratio tends towards lower values, indicating a tendency for inversion.