Type 1 diabetes (insulin-dependent diabetes-mellitus, IDDM) is a disease controlled by the major histocompatibility complex (MHC) which results from T-cell-mediated destruction of pancreatic beta-cells(1). The incomplete concordance in identical twins and the presence of autoreactive T cells and autoantibodies in individuals who do not develop diabetes suggest that other abnormalities must occur in the immune system for disease to result(2,3). We therefore investigated a series of at-risk non-progressors and type 1 diabetic patients (including five identical twin/tripiet sets discordant for disease). The diabetic siblings had lower frequencies of CD4(-)CD8(-)V alpha 24J alpha Q(+) T cells compared with their non-diabetic sibling, All 56 V alpha 24J alpha Q(+) clones isolated from the diabetic twins/triplets secreted only interferon (IFN)-gamma upon stimulation; in contrast, 76 of 79 clones from the at-risk non-progressors and normals secreted both interleukin (IL)-4 and IFN-gamma. Half of the at-risk non-progressors had high serum levels of IL-4 and IFN-gamma. These results support a model for IDDM in which Th1-cell-mediated tissue damage is initially regulated by V alpha 24J alpha Q(+) T cells producing both cytokines; the loss of their capacity to secrete IL-4 is correlated with IDDM.