Responsiveness to IL-2 varies from one lympho-mononuclear subset to another. NK lymphocytes and monocytes spontaneously respond to IL-2 whereas it is generally accepted that T and B lymphocytes need to be activated to fully acquire this competence. To further investigate this phenomenon, we studied human IL-2Rbeta (hIL-2Rbeta) transgenic mice constitutively expressing heterospecific, intermediate-affinity IL-2R (hIL-2Rbeta/mouse IL-2Rgamma(c)). We noted that the B lymphocytes and monocytes from spleens of these hIL-2Rbeta transgenic animals failed to grow when cultured in IL-2-containing medium. Under the same experimental conditions, CD4 lymphocytes survived, again without growth, whereas CD8 lymphocytes and NK cells were able to proliferate and develop potent LAK cytotoxicity. The properties of these CD4 and CD8 lymphocytes were then compared after purification. Both subsets expressed functional IL-2R able to induce global protein phosphorylation and, more precisely, signal transducer and activation of transcription 5 and Erk phosphorylation. Therefore, the differential growth potential of these CD4 and CD8 lymphocytes cannot be explained by the lack of IL-2R-dependent early signaling events. When the entrance of purified CD4 and CD8 lymphocytes into the cell cycle was analyzed, we found that the CD4 lymphocytes were unable to enter the G1 phase in the absence of anti-CD3 stimulation. This correlates with the effect of IL-2 on cyclin-dependent kinase inhibitor p27(kip1). In CD4 lymphocytes, IL-2 does not affect p27(kip1) expression. But in CD8 lymphocytes, IL-2 down-modulates p27(kip1). These results indicate that, aside from IL-2R expression and function, IL-2 responsiveness is also controlled by lineage-specific mechanisms.