Defective inducer T-cell function before the onset of insulin-dependent diabetes mellitus

To investigate the possible role of CD4+ T lymphocyte immunoregulatory abnormalities in the pathogenesis of human insulin-dependent diabetes mellitus (IDD), we studied the in vitro function of CD4+ helper/inducer and suppressor/inducer T-cell subpopulations in 25 high risk non-diabetic individuals who tested positive for islet-cell antibodies (ICA). Helper-inducer T-cell function, as measured in the pokeweed mitogen T-B co-culture system, was decreased in the ICA+ subjects in comparison to controls. This abnormality in helper/inducer T-cell function was present for both IgG (P = 0.0001) and IgM (P = 0.004) secretion by B cells. Diminished helper/inducer function correlated with ICA titer (Pearson correlation coefficient -0.44) with subjects having an ICA titer greater than or equal to 40 JDF units demonstrating the most significant disturbances in function (P = 0.01). The helper/inducer T-cell subset percentage was also decreased in ICA+ subjects when compared to matched controls (30 +/- 3% vs 39 +/- 2%; P = 0.02). The abnormality in helper/inducer function was intrinsic to the CD4+ CD45RA+ subset and was not simply due to diminished numbers of helper/inducer T-cells added in the co-culture experiments, since the defect persisted when CD4+ CD45RA+ helper/inducer T-cells were purified and added to B cells as the only source of T-cell help. Our results indicate that ICA+ subjects have functional defects in the helper/inducer subpopulation of CD4+ T-cells. This abnormality may contribute to the pathogenesis of IDD and may provide a novel marker for identifying persons at risk for developing IDD.