The specific intracellular signaling pathways for interleukin-2 (IL-2) that lead to delivery of the proliferative stimulus are currently unknown. We and others have excluded signaling pathways used by other growth factors and by the antigen-specific T-cell receptor, such as increased intracellular Ca2+ concentrations, activation of protein kinase C, or ion transport across the plasma membrane. One feature of IL-2 signaling that may be important in delivery of the proliferative stimulus is endocytosis and processing of the lymphokine receptor-ligand complex. In this study we examined these steps in receptor signaling by mouse CTLL-2 cells and human OKT3-activated T-cells using monoclonal antibodies specific for the 55 kDa alpha-subunit of the IL-2R that allow IL-2 binding but block endocytosis, and with lysosomotrophic amines that selectively inhibit receptor mediated endocytosis and/or processing of IL-2. Our results demonstrate that these inhibitors block receptor endocytosis, ligand degradation, c-fos protooncogene activation, and ultimately proliferation of the IL-2-dependent T-cell line, CTLL-2. In heterogeneous populations of activated human T cells the lysosomotrophic amines demonstrated a greater inhibition of degradation than of endocytosis. These observations support the hypothesis that IL-2/IL-2R endocytosis and ligand/receptor processing or degradation may be important steps in lymphokine signal transduction.