T helper cell differentiation: on again, off again

Recent studies raise the possibility that T helper (Th) polarization may be attributable to generalized activation and regulated silencing rather than regulated activation of target cytokine genes. The binding of transcription factors GATA-3 or T-bet to specific enhancers does recruit transcription factors such as NFAT-1 to IL-4 or IFNγ promoters, respectively; however, GATA-3 also intrinsically suppresses T-bet and vice versa. Silencing of GATA-3/T-bet, which is influenced by factors such as cytokines, is associated with irreversible Th polarization. For the first few divisions (perhaps reflecting the situation in lymph nodes), naive Th cells retain pluripotency; after further cell divisions (perhaps under the influence of an inflammatory cytokine milieu) they may become polarized appropriately to respond to the specific environment.