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Theranostics 2018; 8(16):4509-4519. doi:10.7150/thno.27428 This issue Cite

Research Paper

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

Alejandra Pera^1,2,✉, Stefano Caserta^3,†, Fabio Albanese¹, Pinar Blowers¹, George Morrow¹, Nadia Terrazzini⁴, Helen E Smith⁵, Chakravarthi Rajkumar¹, Bernhard Reus⁶, James R Msonda^6,7, Murielle Verboom⁸, Michael Hallensleben⁸, Rainer Blasczyk⁸, Kevin A Davies¹, Florian Kern¹

1. Department of Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom.
2. Immunology and allergy GC-01 group Maimonides Biomedicine Institute of Cordoba (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain.
3. Department of Global Health and Infectious Diseases, Brighton and Sussex Medical School, Brighton, United Kingdom.
4. School of Pharmacy and Biomolecular Sciences, University of Brighton.
5. Family Medicine and Primary Care, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
6. School of Engineering and Informatics, University of Sussex, Brighton, UK.
7. University of Malawi, The Polytechnic, Blantyre, Malawi.
8. Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
^†School of Life Sciences University of Hull, Hull, UK.

✉ Corresponding author: Alejandra Pera, PhD, Maimonides Institute for Biomedical Research (IMIBIC), Edificio IMIBIC, avda Menedez Pidal s/n Córdoba, Spain

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 CD28^null T-cells, in particular CD28^null CD4 T-cells. These cells can directly damage endothelium and precipitate cardiovascular events. However, the current paradigm holds that the accumulation of CD28^null 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 CD28^null 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 CD28^null 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 CD28^null T-cell frequencies.

Results: The median frequencies of CD28^null CD4 T-cells and CD28^null 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 CD28^null 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 CD28^null CD4 T-cell expansions (OR=0.108, p=0.003). Over 75% of CMV-reactive CD4 T-cells were CD28^null.

Conclusion: CMV infection and HLA type are major risk factors for CD28^null CD4 T-cell-associated cardiovascular pathology. Increased numbers of CD28^null 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.

Keywords: CD28^null CD4 T-cells, CD28^null CD8 T-cells, cardiovascular disease, aging, Cytomegalovirus, coronary complications

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