Recent studies using IL-2R alpha knockout mice have generated conflicting results regarding the hypothesis that IL-2/IL-2R interaction is obligatory for the development of AICD, which plays a central and pivotal role in maintaining peripheral tolerance. A relevant consequence of AICD defect is the demonstrated development of autoimmune lymphoproliferative disease in IL-2, IL-2R alpha, and IL-2R beta knockout mice, but not in IL-4, IL-7, or IL-7R knockout mice. Whether IL-4, IL-7, or IL-15 can provide the required signal for AICD development is addressed here using IL-2 and IL-2R beta knockout mice. Lymph node T cells from knockout mice were stimulated with Con A plus rIL-1 for 3 days and then maintained in high concentrations of rIL-4, rIL-7, or rIL-15 for an additional 3 days before they were subjected to AICD analysis. Our study demonstrates that IL-4, IL-7, and IL-15 can transduce signals critical for AICD development in the absence of IL-2-mediated signals. The requirement for relatively high concentrations of these lymphokines suggests their limited role in maintaining peripheral T cell tolerance, thus explaining the differential expression of autoimmune lymphoproliferative disease in the targeted mutant strains described above.