Cell division is not a "clock" measuring acquisition of competence to produce IFN-gamma or IL-4

Naive CD4 T cells acquire the potential to produce IFN-gamma and IL-4 by cu lture in the presence of their cognate Ag, APC, and appropriate cytokines. In this study, we show that commitment to IFN-gamma production on the part of rigorously purified naive CD4 T cells can occur without cell division. I ndeed, even entry into S phase is not essential, Moreover, both CD4 and CD4 /CD8 thymocytes from TCR-transgenic mice (5CC7 mice) on a Rag2(-/-) backgro und can acquire IFN-gamma -producing capacity when stimulated by peptide, A PC, and IL-12. These cells can do so without dividing and some acquire IFN- gamma -producing activity without entry into S phase. Not only is cell divi sion not required for acquisition of cytokine-producing potential, cell pop ulations that have undergone the same numbers of divisions can have quite d ifferent proportions of IFN-gamma- or IL-4-producing cells, depending on th e duration of priming or, in the case of IL-4, on the concentration of pept ide. Thus, cell division is not a clock for the expression of these cytokin es. Factors associated with priming conditions including strength of stimul ation, duration of priming, and number of divisions each play a role.