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

Cell growth and proliferation as well as cell cycle arrest and apoptosis al l play integral roles in the cellular immune response. The signals that lea d to cytokine production by antigen- or mitogen-stimulated T cells have bee n 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 compet ence and progression phases to examine quantitative and qualitative differe nces 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 concentrati ons of phytohemagglutinin (PHA) or they were stimulated to proliferate usin g mitogenic concentrations of PHA. The competent state (that is, the capaci ty to proliferate in response to exogenous IL-2) was characterized by calci um mobilization, a protein kinase C-dependent internalization of CD3, incre ased mitogen-activated protein kinase (MAPK) activity, transient translocat ion of AP-1 transcription factors to the nucleus, expression of immediate e arly genes, activation of G1-phase cyclin-dependent kinases, and increased CD25 (IL-2R alpha) expression. However, all of these events were of lesser magnitude in T cells rendered competent than in T cells stimulated to proli ferate. Furthermore, the mitogenic stimulus induced a different pattern of MAPK activation and sustained translocation of AP-1 to the nucleus with con comitant IL-2 production. The data indicate that quantitative and qualitati ve 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. (C) 1999 Academic Press.