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 primary response to antigen, often giving rise to effector populations with a polarized type 1 or type 2 cytokine profile. However, polarization is not a simple choice between two differentiation pathways. This article reviews the evidence, particularly from single-cell and clonal studies, that polarization is the outcome of a series of stochastic events whose probabilities are determined in part by genetic background and in part by extracellular signals 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 effects on clonal expansion and chromatin remodeling, CpG demethylation and transcriptional activation of cytokine genes. Polarization is, therefore, achieved at the population level by altering frequencies of expression among cells with many different expression patterns, rather than by selective differentiation of a discrete subset. Type 1 and type 2 populations progressively lose responsiveness to counter-polarizing stimuli. While the molecular basis of this process is not yet known, the observed persistence of cells with flexible cytokine profiles in some polarized populations suggests that loss of flexibility may also be a probabilistic event.