Fight Aging!

The aging of the immune system isn't just a matter of becoming vulnerable to commonplace infectious diseases, such as influenza. The immune system also removes senescent cells and cancerous cells, both of which present sizable risks to health in later life. Additionally, immune cells participate in normal tissue maintenance in a variety of ways. Further, the chronic inflammation characteristic of an aged immune system disrupts the normal function of many types of cell and tissue, contributing to a diverse range of age-related conditions.

For most people, cytomegalovirus (CMV) is an apparently innocuous persistent herpesvirus infection, one that presents no obvious symptoms. A good deal of evidence supports a sizable role for CMV in the age-related decline of the immune system into inflammatory overactivation (inflammaging) and incapacity (immunosenescence), however. Most people are exposed to CMV at some point during their lives, and the immune system is incapable of clearing this persistent virus. Over time, ever more T cells of the adaptive immune system become devoted to targeting CMV rather than taking on other threats, and may even become harmful themselves as result of too much replication in response to the presence of CMV In effect, CMV actively corrodes the ability of the adaptive immune system to defend the body from other threats.

In today's open access paper, researchers provide more supporting evidence for potentially detrimental changes in T cell populations to occur due to CMV infection in older individuals rather than due to aging per se. The specific change that is the focus of the paper is likely also protective, an attempt to contain CMV, that nonetheless results in pathology. It is unclear as to whether an approach to effectively clear CMV from the body would undo this damage naturally, or whether some way of removing the unwanted T-cells would be required to restore balance to the aged immune system. Both of these types of therapy are prospects for the foreseeable future, but it is fair to say that much more attention is given to the development of antivirals for persistent infections than is given to the targeted destruction of immune cells.

Functional Changes of T-Cell Subsets with Age and CMV Infection

T-cells are a major component of adaptive immunity, with a high degree of specificity in response to a pathogen challenge, enabling the host to mount a specific immune response and generate immunological memory. Therefore, for effective immune protection against the primary and subsequent challenges, these cells must be maintained in a unimpaired state and appropriately regulated. However, on aging, the immune system undergoes profound changes, loosely termed immunosenescence, that can affect the outcome of the immune response. The impact of these age-related changes on the immune system has been associated clinically with decreased efficacy of vaccines, an increase in the frequency and severity of infectious diseases, and an increased incidence of chronic inflammatory disorders. These alterations are associated with phenotypical and functional changes affecting a variety of immune cells, especially T-cells. It has been shown that chronic stimulation of the immune system, such as by persistent viral infections, associates with age-related alterations in the peripheral T-cell pool. Chronic infection especially by cytomegalovirus (CMV) has a dramatic influence on the T-cell compartment, both on CD8+ and CD4+ T-cells.

In humans, repetitive replication of T-cells is associated with the loss of CD28 and the acquisition of CD57. Thus, CD28- and CD57+ T-cells are considered to be late- or terminally differentiated T-cells characterized by low telomerase activity and shorter telomeres compared with CD28+CD57- T-cells. At least some of these CD28-CD57+ T-cells may be senescent. It has been shown that besides age, persistent CMV infection is also associated with the accumulation of these highly differentiated T-cells. Accumulating evidence supports a detrimental role of senescent T-cells in several chronic inflammatory clinical conditions, including cardiovascular diseases such as atherosclerosis and myocardial infarction.

Our results show that in middle-aged and older overtly healthy individuals, the main factor driving the expansion of CD57+ T-cells is CMV infection. However, from the fourth decade onwards, these cells do not accumulate further with age. In previous work, we showed that the percentage of CD8+CD57+ T-cells was similar between young and middle-aged CMV-seropositive individuals. Therefore, here, we extend our previous findings to show that CD57 expression by T-cells is not only a hallmark of CMV infection in young individuals but also at older ages. Accordingly, once CMV infection takes place, CD57+ T-cells will expand, and after that, their percentage will remain rather stable over time. Thus, our results argue against the consensus that the expansion of these cells is a sign of chronological aging.

Our results regarding CD4+CD57+ T-cell expansions with CMV infection are also in agreement with the observation that CMV, but not aging, has a significant effect on the expansion of pro-atherogenic CD4+CD28- T-cells. These cells (that also express CD57) are cytotoxic, capable of causing vascular damage, and their expansion is associated with autoimmune and cardiovascular disease. Higher frequencies of CD4+CD57+ T-cells have been associated with poorer prognosis in several diseases. In acute heart failure patients, high percentages of these cells are associated with the development of cardiovascular events (defined as heart failure-associated mortality, transplantation, or rehospitalization). In end-stage renal disease patients, the frequency of CD4+CD57+ T-cells is associated with atherosclerotic changes, and in multiple sclerosis, their frequency is associated with disease severity and poorer prognosis.

Therefore, immunological treatments should consider both age and CMV infection as a major factor. This strengthens the need for validation studies with not only the aim to present something novel but also to confirm findings in different populations. The association of these T-cell expansions with CMV infection and disease underlines the necessity of considering CMV serology in any study regarding immunosenescence and emphasizes that the price of immune protection is always some degree of immunopathology.