Educating T cells: Early events in the differentiation and commitment of cytokine-producing CD4(+) and CD8(+) T cells

T lymphocytes acquire the ability to synthesize cytokines during their prim ary response to antigen, often giving rise to effector populations with a p olarized type 1 or type 2 cytokine profile. However, polarization is not a simple choice between two differentiation pathways. This article reviews th e evidence, particularly from single-cell and clonal studies, that polariza tion is the outcome of a series of stochastic events whose probabilities ar e determined in part by genetic background and in part by extracellular sig nals received during activation and clonal expansion. The data suggest that these extracellular signals independently and differentially regulate the probability of expression of each cytokine gene, for example by their effec ts on clonal expansion and chromatin remodeling, CpG demethylation and tran scriptional activation of cytokine genes. Polarization is, therefore, achie ved at the population level by altering frequencies of expression among cel ls with many different expression patterns, rather than by selective differ entiation of a discrete subset. Type 1 and type 2 populations progressively lose responsiveness to counter-polarizing stimuli. While the molecular bas is of this process is not yet known, the observed persistence of cells with flexible cytokine profiles in some polarized populations suggests that los s of flexibility may also be a probabilistic event.