INSULIN-DEPENDENT diabetes mellitus is widely believed to be an autoimmune disease¹. Recent onset diabetics show destruction of insulin-secreting pancreatic β -cells associated with a lymphocytic infiltrate (insulitis) ², with autoantibodies to β-cells being found even before the onset of symptoms³. Susceptibility to the disease is strongly influenced by major histocompatibility complex (MHC) class II polymorphism in both man⁴ and experimental animal models such as the non-obese diabetic (NOD) mouse⁵. As MHC class II molecules are usually associated with dominant immune responsiveness, it was surprising that introduction of a transgenic class II molecule, I–E, protected NOD mice from insulitis and diabetes⁶. This could be explained by a change either in the target tissue or in the T cells presumed to be involved in β-celI destruction. Recently, several studies have shown that I–E molecules are associated with ontogenetic deletion of T cells bearing antigen/MHC receptors encoded in part by certain T-cell receptor Vβ gene segments^7–11. To determine the mechanism of the protective effect of I–E, we have produced cloned CD4⁺ and CD8⁺ T-cell lines from islets of recently diabetic NOD mice. These cloned lines are islet-specific and pathogenic in both I–E⁻ and I–E+ mice. Both CD4⁺ and CD8⁺ cloned T cells bear receptors encoded by a Vβ5 gene segment, known to be deleted during development in I–E expressing mice¹⁰. Our data provide, therefore, an explanation for the puzzling effect of I–E on susceptibility to diabetes in NOD mice.