JAK-STAT signaling and the generation of Th1 and Th2 cells. Following antigen presentation, a naive CD4+ T cell will differentiate along the Th1 or Th2 pathway, depending on the nature of the cytokines it contacts. Signaling through the IL-12 receptor (red pathway) and its associated Jak and Stat proteins culminates in the expression of Th1-specific gene products, particularly the cytokine interferon-γ (IFN-γ) Conversely, IL-4 activates a distinct receptor complex, containing different Jaks and Stats, and favors the expression of Th2 cytokines and other gene products (black pathway). These pathways can regulate one another at the transcriptional level. In particular, the transcription factor GATA3, whose expression is induced by IL4 signaling, is essential for the transactivation of other Th2-associated genes, such as those for Th2 cytokines and chemokine receptors. Another transcription factor, T-BET, is induced by IFN-γ (and therefore indirectly by IL-12 stimulation) and also favors expression of this cytokine — thus establishing a positive feedback loop that supports Th1 polarization. In addition, T-BET silences expression of Th2-associated genes. Polarization toward the Th2 response leads to the expression of various cytokines — IL-4, IL-5, IL-6, IL-10, and IL-13 — that contribute to the pathologies seen in asthma.