EXTREME TH1 BIAS OF INVARIANT V-ALPHA-24J-ALPHA-Q T-CELLS IN TYPE-1 DIABETES

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