Expansion of cytolytic CD4+CD28− T cells in end-stage renal disease

Cytomegalovirus (CMV) seropositivity is associated with increased risk for atherosclerotic disease in patients with end-stage renal disease. This association is due to a unique peripheral blood CD4(+) T cell population which lack CD28 (CD4(+)CD28(-) T cells). Here we found that this patient population has a significant age-dependent increase of CD4(+)CD28(-) T cells that comprise over half of the circulating CD4 T cells in some. Patients over 50 years of age have a 50-fold higher percentage of CD4(+)CD28(-) T cells compared to seronegative patients and a 5-fold higher percentage when compared to seropositive healthy controls. Stimulation by CMV-antigen or by polyclonal stimulation using PMA and ionomycin showed that CD4(+)CD28(-) cells in patients with end stage renal disease degranulated and secreted interferon gamma thus indicating that they are cytolytic. The average anti-CMV IgG titer displayed a remarkable age-dependent increase only in patients with end stage renal disease. These findings are highly suggestive of repetitive antigenic stimulation of the immune system in patients with end stage disease by subclinical CMV reactivation which might contribute to increased atherosclerotic risk.