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Title: CD28 null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death
Authors: Pera, Alejandra
Caserta, Stefano
Albanese, Fabio
Blowers, Pinar
Morrow, George
Terrazzini, Nadia
Smith, Helen Elizabeth
Rajkumar, Chakravarthi
Reus, Bernhard
Msonda, James R
Verboom, Murielle
Hallensleben, Michael
Blasczyk, Rainer
Davies, Kevin A
Kern, Florian
Keywords: CD28 null CD8 T-cells
CD28 null CD4 T-cells
Issue Date: 2018
Source: Pera, A., Caserta, S., Albanese, F., Blowers, P., Morrow, G., Terrazzini, N., . . . Kern, F. (2018). CD28 null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death. Theranostics, 8(16), 4509-4519. doi:10.7150/thno.27428
Series/Report no.: Theranostics
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.
DOI: 10.7150/thno.27428
Rights: © 2018 Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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