Persistent activation of CD8+ T-cells characterizes prediabetic twins.
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.


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.
Department of Immunology, King's College School of Medicine and Dentistry, London, U.K.
M
M
Peakman
R D
RD
Leslie
L
L
Alviggi
M
M
Hawa
D
D
Vergani
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004200:Diseases in Twins; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology*; D011446:Prospective Studies; D012016:Reference Values; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014430:Twins, Monozygotic
D017252:CD3 Complex; D006684:HLA-DR Antigens