Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets

Naive CD4(+) T cells activated through TCR/CD28 under Th1 or Th2 conditions expressed canonical cytokine patterns irrespective of cell division. Only cells that had divided fewer than four times were capable of reexpressing a lternative cytokines when restimulated under opposing conditions. Although T cells transcribed both IFN-gamma and IL-4 within hours in a Stat4-/Stat6- independent manner, neither T-bet nor GATA-3 was induced optimally without Stat signals, and polarized cytokine expression was not sustained. Cytokine genes were positioned apart from heterochromatin in resting T cell nuclei, consistent with rapid expression. After polarization, the majority of sile nced cytokine alleles were repositioned to heterochromatin. Naive T cells t ransit through sequential stages of cytokine activation, commitment, silenc ing, and physical stabilization during polarization into differentiated eff ector subsets.