Using phytohemagglutinin (PHA)-activated human T lymphocytes, we have demonstrated de novo emergence of growth factor receptors (insulin, insulin-like growth factor-1 [IGF-1], and interleukin-2 [IL-2]) in the CD4(+) and CD8(+) subsets determined by flow cytometry. This activation was also associated with development of insulin-degrading activity (IDA) in a time-dependent fashion. These events, which are actinomycin- and cycloheximide-sensitive, occur only in activated, but not nonactivated, CD4(+) and CD8(+) lymphocytes. The emergence of these receptors, as well as IDA, which is preceded by CD69 emergence, reaches a plateau by 72 hours and is comparable in both subsets. The IDA is localized in the cytosol, and insulin binding is limited to the cell membrane. T-lymphocyte activation also initiates expression of the IL-2 gene with the transcription of IL-2 mRNA, the level of which is further enhanced by 38% with the addition of insulin. In these activated lymphocytes, insulin binding to its receptor also caused an 83% upregulation of phosphorylated insulin receptor substrate-1 (IRS-1). In situ development of these growth factor receptors and signal transduction mechanisms in T lymphocytes upon activation, such as by proinflammatory cytokines or oxidative stress, could be an important defense mechanism in various disease states in man.