CD4+CD28- T-cell expansion in Wegener's granulomatosis is driven by latent CMV and is associated with an increased risk of infection and mortality.

OBJECTIVE: Expanded populations of CD4+CD28- T-cells with a cytotoxic phenotype have been repeatedly reported in patients with Wegener's granulomatosis (WG). In healthy individuals expansion of this T-cell population follows cytomegalovirus (CMV) infection. We investigated whether CMV infection may be responsible for driving the expansion of CD4+CD28- T-cells in WG patients and how this might relate to clinical features. METHODS: 48 WG patients and 38 age matched healthy donors were included in the study. CMV-specific immunoglobulin G in serum was detected by ELISA. Flow cytometric analysis was used to study T-cell populations and phenotype. The presence of CMV in renal biopsy tissue from WG patients was investigated by immunohistochemistry and PCR. Clinical information was obtained from patient records. RESULTS: Populations of CD4+CD28- T-cells were only expanded in CMV seropositive WG patients and controls. In CMV seropositive WG patients we observed negative correlations between the percentages of CD4+CD28- T-cells and naive T-cells and glomerular filtration rate at presentation. There was a positive correlation between the percentage of CD4+ CD28- T-cells and risk of infection and mortality. CMV could not be detected in renal tissue by PCR or immunohistochemistry. In a cohort of 182 anti-neutrophil cytoplasmic antibody associated vasculitis clinical trial patients CMV seropositivity itself was not a risk factor for infection. CONCLUSION: The expansion of CD4+CD28- T-cells in WG patients is associated with CMV infection and leads to a reduction in the number of naïve T-cells in peripheral blood. Patients with expanded CD4+CD28- T-cells have a significantly increased mortality and infection risk.