Persistent Activation of CD8+ T-cells Characterizes Prediabetic Twins

Abstract

OBJECTIVE Elevated circulating levels of activated CD3+ T-cells are characteristic of type I diabetes at diagnosis, and activated CD8+ (cytotoxic/suppressor) T-cells predominate in the islet infiltrate. The aim of this study was to examine the peripheral blood of prediabetic and nondiabetic identical twins of patients with type I diabetes for the presence of activated CD8+ T-cells and by comparing these groups, analyze the relationship of such cells to the development of the disease. RESEARCH DESIGN AND METHODS In a 10-year prospective study, blood T-cell subsets (CD3+ total T-cells, CD4+ helper/inducer, and CD8+ cytotoxic/suppressor) were analyzed for evidence of activation (cell surface expression of HLA-DR, CD25) in 18 identical twins of patients with type I diabetes, 8 of whom became diabetic (prediabetic twins), while 10 remained nondiabetic after at least 8 years of follow-up and are now at low risk for type I diabetes. Fifteen healthy individuals were studied as control subjects. RESULTS At the beginning and during the study, percentage levels of activated CD3+ HLA-DR+ T-cells were significantly elevated in prediabetic and low-risk twins compared with control subjects (P < 0.005) but remained high only in prediabetic twins (P < 0.005). Both prediabetic and low-risk twins had elevated levels of HLA-DR+ CD4+ T helper cells compared with control subjects throughout the study (P < 0.001), and these remained high in both (P < 0.001 and P < 0.05, respectively). Only prediabetic twins had elevated levels of HLA-DR+ CD8+ T-cells during the study. These were significantly higher than in control subjects (P < 0.005) and low-risk twins (P < 0.05) and remained persistently elevated to diagnosis (P < 0.001). Abnormally elevated levels of HLA-DR+ CD8+ T-cells in twins indicate a 50% risk of progression to type I diabetes by life-table analysis (P = 0.01), with a positive predictive value of 100%, sensitivity of 50%, and specificity of 100%. Elevated CD25+ T-cell levels in prediabetic and low-risk twins were less marked and less able to discriminate between the twin groups. CONCLUSIONS These results demonstrate that prediabetes is characterized by persistent elevation of HLA-DR+ CD8+ T-cells with the same cytotoxic phenotype as cells predominating in the islet at diagnosis, suggesting that the circulating cells may have a role in the pathogenesis of islet damage.