Quantitative and qualitative signals determine T-cell cycle entry and progression

Cell growth and proliferation as well as cell cycle arrest and apoptosis all play integral roles in the cellular immune response. The signals that lead to cytokine production by antigen- or mitogen-stimulated T cells have been studied in detail. However, it is not fully understood how these signals promote cell cycle entry and progression to DNA synthesis in T lymphocytes, especially in primary cells. We used a model distinguishing between competence and progression phases to examine quantitative and qualitative differences in signal transduction that resulted in cell cycle entry and G1 phase arrest or led to DNA synthesis in human T cells. Resting peripheral blood T cells were rendered competent by stimulation with submitogenic concentrations of phytohemagglutinin (PHA) or they were stimulated to proliferate using mitogenic concentrations of PHA. The competent state (that is, the capacity to proliferate in response to exogenous IL-2) was characterized by calcium mobilization, a protein kinase C-dependent internalization of CD3, increased mitogen-activated protein kinase (MAPK) activity, transient translocation of AP-1 transcription factors to the nucleus, expression of immediate early genes, activation of G1-phase cyclin-dependent kinases, and increased CD25 (IL-2Ralpha) expression. However, all of these events were of lesser magnitude in T cells rendered competent than in T cells stimulated to proliferate. Furthermore, the mitogenic stimulus induced a different pattern of MAPK activation and sustained translocation of AP-1 to the nucleus with concomitant IL-2 production. The data indicate that quantitative and qualitative differences in early signaling events distinguish the acquisition of the competent state or the induction of cytokine production with a commitment to T-cell proliferation.