DEVELOPMENTAL COMMITMENT TO THE TH2 LINEAGE BY EXTINCTION OF IL-12 SIGNALING

Developmental commitment to Th1 or Th2 responses critically influences host susceptibility to particular pathogens. We describe a novel mech anism governing stable commitment to Th2 differentiation. Naive T cell s develop strongly polarized Th1 and Th2 profiles by 7 days after acti vation. However, commitment of these developing cells differs substant ially. Although IL-4 reverses early Th1 differentiation, IL-12 cannot reverse early Th2 differentiation. Th1 reversibility results from main tenance of IL-4 signal transduction, whereas Th2 commitment results fr om rapid loss of IL-12 signaling. The IL-12 signaling defect in Th2 ce lls results in failure to phosphorylate Jak2, Stat3, and Stat4. Since Th2 cells express the mRNA for the cloned murine IL-12 receptor beta s ubunit, the signaling defect may involve expression or function of uni dentified receptor components. The rapid extinction of IL-12 signaling in Th2 cells provides a demonstration of a mechanism for the stable c ommitment to a T helper phenotype.