CD28^null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death

Abstract

An increased risk of cardiovascular death in Cytomegalovirus (CMV)-infected individuals remains unexplained, although it might partly result from the fact that CMV infection is closely associated with the accumulation of CD28null T-cells, in particular CD28null CD4 T-cells. These cells can directly damage endothelium and precipitate cardiovascular events. However, the current paradigm holds that the accumulation of CD28null T-cells is a normal consequence of aging, whereas the link between these T-cell populations and CMV infection is explained by the increased prevalence of this infection in older people. Resolving whether CMV infection or aging triggers CD28null T-cell expansions is of critical importance because, unlike aging, CMV infection can be treated.Methods: We used multi-color flow-cytometry, antigen-specific activation assays, and HLA-typing to dissect the contributions of CMV infection and aging to the accumulation of CD28null CD4 and CD8 T-cells in CMV+ and CMV- individuals aged 19 to 94 years. Linear/logistic regression was used to test the effect of sex, age, CMV infection, and HLA-type on CD28null T-cell frequencies.Results: The median frequencies of CD28null CD4 T-cells and CD28null CD8 T-cells were >12-fold (p=0.000) but only approximately 2-fold higher (p=0.000), respectively, in CMV+ (n=136) compared with CMV- individuals (n=106). The effect of CMV infection on these T-cell subsets was confirmed by linear regression. Unexpectedly, aging contributed only marginally to an increase in CD28null T-cell frequencies, and only in CMV+ individuals. Interestingly, the presence of HLA-DRB1*0301 led to an approximately 9-fold reduction of the risk of having CD28null CD4 T-cell expansions (OR=0.108, p=0.003). Over 75% of CMV-reactive CD4 T-cells were CD28null.Conclusion: CMV infection and HLA type are major risk factors for CD28null CD4 T-cell-associated cardiovascular pathology. Increased numbers of CD28null CD8 T-cells are also associated with CMV infection, but to a lesser extent. Aging, however, makes only a negligible contribution to the expansion of these T-cell subsets, and only in the presence of CMV infection. Our results open up new avenues for risk assessment, prevention, and treatment.

Immunosenescence Study of T Cells: A Systematic Review

“…In contrast, the effect of age on CD28 − CD4 and CD8 T cells is small. They concluded that the diminished expression of CD28 in T cells strongly suggests that these observations reflect CMV-associated immunomodulation rather than normal immunosenescence ( 57 ).…”

Generation, maintenance and tissue distribution of T cell responses to human cytomegalovirus in lytic and latent infection

“…The evidence from these studies has been used by some to support the hypothesis that an increase in the size of the CMV memory T cell population over time in humans is indicative of memory inflation. However, other studies have shown that large expansions in the frequency of CMV-specific memory T cells is a feature of being CMV positive irrespective of age, including studies of children as well as younger adults [51, 63–67], this is also true when observing the absolute size of the memory T cell compartment [23, 52].…”

CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

“…Expansions of these cells have long been associated with CMV infection, but the strength of the association between large numbers of these cells and CMV infection was grossly underestimated. Only in the presence of CMV infection do individuals exhibit cell numbers typically associated with clinical disease in the literature (usually several percent) 74 . A recent publication reported that treatment with ganciclovir in CMV + patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis reduced the number of CD28 null CD4 T cells 75 .…”