An instructive component in T helper cell type 2 (Th2) development mediated by GATA-3

Although interleukin (IL)-12 and IL-4 polarize naive CD4(+) T cells toward T helper cell type 1 (Th1) or Th2 phenotypes, it is not known whether cytok ines instruct the developmental fate in uncommitted progenitors or select f or outgrowth of cells that have stochastically committed to a particular fa te. To distinguish these instructive and selective models, we used surface affinity matrix technology to isolate committed progenitors based on cytoki ne secretion phenotype and developed retroviral-based tagging approaches to directly monitor individual progenitor fate decisions at the clonal and po pulation levels. We observe IL-4-dependent redirection of phenotype in cell s that have already committed to a non-IL-4-producing fate, inconsistent wi th predictions of the selective model. Further, retroviral tagging of naive progenitors with the Th2-specific transcription factor GATA-3 provided dir ect evidence for instructive differentiation, and no evidence for the selec tive outgrowth of cells committed to either the Th1 or Th2. fate. These dat a would seem to exclude selection as an exclusive mechanism in Th1/Th2 diff erentiation, and support an instructive model of cytokine-driven transcript ional programming of cell fate decisions.