Interleukin-2-mediated survival and proliferative signals are uncoupled in T lymphocytes that fail to divide after activation

T lymphocytes are heterogeneous with respect to their ability to proliferate following activation in vitro and in vivo. Approximately 30% of T lymphocytes fail to progress through the cell cycle, despite showing evidence of an activated state. The population of T lymphocytes that remains undivided during a primary stimulation has been shown to be refractory to restimulation via the TCR and fails to proliferate in response to IL-2. In an in vitro model of T-cell deletion following clonal expansion, we demonstrate that T lymphocytes that do not progress through the cell cycle during primary stimulation have a sevenfold greater survival advantage compared with T lymphocytes that have divided. Progression through multiple division cycles is associated with down-regulation of Bcl-2 during a postactivation period of growth factor withdrawal. However this alone does not account for diminished survival, as constitutive expression of a Bcl-2 transgene did not restore survival to the levels seen in undivided cells. Engagement of the IL-2 receptor on these undivided activated T lymphocytes leads to enhanced survival and up-regulation of Bcl-2 and Bcl-x_L. Surprisingly, while IL-2 also induces phosphorylation of Akt, it does not initiate cell cycle progression in this population of primary undivided cells. Our data provide evidence that a T cell's survival capacity is linked to its proliferative behavior. Furthermore, our results provide the first report of a population of T cells, in which the IL-2 receptor-mediated signaling pathways leading to survival and proliferation are naturally uncoupled.