Transgenic mice expressing murine interleukin (IL)-2 constitutively in islet beta cells were generated (RIP-IL-2 mice). They died at an early age, when higher levels of IL-2 were produced, because of a predominant macrophage inflammatory response that destroyed the exocrine pancreas. Animals with lower levels of IL-2 survived and had islets that became increasingly infiltrated with lymphocytes over time. However, in spite of the presence of impressive peri- and intra-islet infiltrates, autoimmunity to islet antigens was not seen. Autoimmunity was also not induced to extrathymic H-2Kb molecules known to induce tolerance by a peripheral mechanism when the RIP-IL-2 mice were mated to other mice expressing H-2Kb in islet beta cells (RIP-Kb mice). Apparently, IL-2 can act only on activated T cells and is unable to reverse tolerance in T cells that have been made unresponsive through inappropriate presentation of antigen.