Two- and three-color cytofluorimetric techniques were used to study the expression patterns of the activation antigen HLA-DR on peripheral blood immunoregulatory T-cells from 25 patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM) and 14 age- and sex-matched control subjects. The mean percentage of total activated (CD3+HLA-DR+) T-cells was significantly elevated in the IDDM group compared with the control group (P < 0.001). In control subjects, basal activation of CD4+ and CD8+ lymphocytes accounted for the low percentage levels of activated T-cells. In contrast, the majority of IDDM patients showed an unbalanced activation of CD4+ and CD8+ lymphocytes with predominant activation of the CD8+ lymphocyte subset. The composition of the activated T-cell fraction was dependent on the composition of the total (activated + nonactivated) T-cell population, as indicated by the positive correlation between the CD4+/CD8+ T-cell ratios in these two cell populations (r = 0.714; P < 0.001). Excessive activation of CD8+ T-cells was attributable to similar increases in the proportions of CD8+CD45RA+HLA-DR+ (naive) and CD8+CD45RAHLA-DR+ (memory) cells. Analysis of the CD11b-defined subsets revealed predominant activation of CD8+ CD11b (cytotoxic) T-cells; CD8+CD16+ HLA-DR+ natural killer cells wereunchanged. The distribution of HLA-DR+ cells among subsets of CD4+ T-cells differed from the pattern in the CD8+ population in that selective activation of CD4+ CD45RA (memory, helper-inducer) cells accounted for the small increase in activated CD4+ cells. The present findings suggest an important role for CD8+ T-lymphocytes in IDDM and raise the possibility that these lymphocytes might be the relevant target for early immunotherapy in patients with recent disease onset.

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