Pera, AlejandraCaserta, StefanoAlbanese, FabioBlowers, PinarMorrow, GeorgeTerrazzini, NadiaSmith, Helen ERajkumar, ChakravarthiReus, BernhardMsonda, James RVerboom, MurielleHallensleben, MichaelBlasczyk, RainerDavies, Kevin AKern, Florian2023-01-252023-01-252018-07-18Pera A, Caserta S, Albanese F, Blowers P, Morrow G, Terrazzini N, et al. CD28null pro-atherogenic CD4 T-cells explain the link between CMV infection and an increased risk of cardiovascular death. Theranostics. 2018 Aug 7;8(16):4509-4519http://hdl.handle.net/10668/12942An 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.enAttribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/CD28null CD4 T-cellsCD28null CD8 T-cellsCytomegalovirusAgingCardiovascular diseaseCoronary complicationsAdultAgedAged, 80 and overAgingCD28 antigensCD4-positive T-lymphocytesCytomegalovirus infectionsFemaleFlow cytometryHeart failureHistocompatibility testingHumansMaleMiddle agedPrevalenceRisk factorsYoung adultresearch article30214635open accessAntígenos CD28Citometría de flujoEnvejecimientoFactores de riesgoInfecciones por CitomegalovirusInsuficiencia cardíacaLinfocitos T CD4-positivos10.7150/thno.274281838-7640PMC6134924https://doi.org/10.7150/thno.27428https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134924/pdf