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Harmful T Cells Explain the Link Between Cytomegalovirus Infection and Raised Cardiovascular Risk

Persistent cytomegalovirus (CMV) infection is thought to cause a sizable amount of the age-related decline of the immune system. Latent infection by this sort of herpesvirus causes few to no immediate and obvious symptoms in the vast majority of individuals, but the virus cannot be permanently cleared by the immune system. Over time ever more T cells of the adaptive immune system become uselessly specialized to CMV, unavailable for other tasks. Coupled with the much reduced pace of creation of new T cells in later life, this results in an increasingly dysfunctional immune system.

Researchers here point to one specific consequence of the accumulation of a problematic class of T cell noted to occur with aging, increased risk of cardiovascular disease, and present evidence to show that this accumulation occurs because of persistent CMV infection. All told, the evidence for CMV to be a major issue, a slow corrosion of immune function and health, is quite compelling. What to do about it? The most effective approach might not be to tackle CMV directly, but rather to clear out and replace the problem immune cells via some form of targeted cell destruction followed by cell therapy.

A recent publication shows that Cytomegalovirus (CMV) infection increases the risk of cardiovascular death by over 20% but no specific mechanisms explaining this effect were identified. CMV infection, however, is notorious for promoting large expansions of terminally differentiated effector T-cells, including CD4 T-cells. This is particularly observable in older people. Moreover, there is good evidence that terminally differentiated T-cells may cause vascular damage, to the extent that therapies specifically targeting T-cells in advanced atherosclerosis are being developed.

Among activated CD4 T-cells, cardiologists are particularly interested in CD28null CD4 T-cells. These terminally differentiated effector cells do not express CD28, a co-stimulatory receptor molecule, which antigen-presenting cells engage during early T-cell activation. CD28null CD4 T-cells were initially discovered in rheumatoid arthritis, but later associated with unstable angina and coronary artery plaque instability. Multiple links between these cells and cardiovascular complications have since been reported. Down-regulation of CD28 on CD4 T-cells is thought to be triggered by continuous/repetitive antigen exposure, which could be the result of a persistent viral infection, for example with CMV.

CD28null CD4 T-cells accumulate in older people and show reduced proliferative capacity among many other signs of cellular senescence. Large frequencies of these cells are, therefore, primarily attributed to normal (immune system) aging. While an association of CMV infection with increased numbers of CD28null CD4 T-cells was repeatedly reported in the literature, this link is generally considered to be indirect and explained by the fact that older people are more likely to be CMV infected. Nobody has yet studied CD28null CD4 or CD8 T-cells in a large enough number of CMV-seronegative (CMV-) older people to resolve this issue. However, several smaller studies in the fields of autoimmune and cardiovascular disease offer some insight.

It was not the purpose of our work to show that CD28null CD4 T-cells are associated with cardiovascular (CV) morbidity or mortality, since there is overwhelming evidence for this association in the literature. Instead, we examined the frequencies of CD28null CD4 T-cells in 93 CMV- and 122 CMV+ generally healthy older people and a corresponding cohort of young people; CD28null CD8 T-cells were evaluated in parallel. Our investigation was focused on the intriguing possibility that, independently of aging, CMV infection is a major risk factor for the expansion of the highly pro-atherogenic CD28null CD4 T-cell subset.

Our results show that CMV infection is significantly associated with the accumulation of CD28null CD4 T-cells. Our data further suggest that CMV may directly drive this subset with a significant proportion of these cells recognizing CMV-antigens. The frequencies of CD28null CD4 T-cells were an order of magnitude higher in CMV+ compared to CMV- individuals, but only marginally affected by age. These observations seem to refute the idea that accumulation of CD28null CD4 T-cells is a result of normal immune system aging.

Link: https://doi.org/10.7150/thno.27428

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