Interleukin-4 is a prototypic type I cytokine that is a central regulator of allergic inflammatory responses. It controls the polarization of naive CD4 T cells to the TH2 phenotype and Ig class switching to IgE. The Cytokine Biology Unit has characterized the signaling mechanisms utilized by the IL-4 receptor. It has been shown that activation of the latent transcription factor, Stat 6, controls both TH2 polarization and IgE class switching. In addition, IL-4-mediated Stat6 activation rescues activated naive CD4 T cells from apoptosis. During the past year, scientists in the Unit have gained insight into why low doses of antigen favor Th2 over Th1 differentiation. Using a highly controlled T cell receptor transgenic model, it has been shown that the degree of activation of the MAP kinase erk plays a critical role both by determining the transcription of the key IL-4-inducing transcription factor Gata 3 and by contributing to the early opening of the Il4 gene. High doses, by causing vigorous activation of erk, suppress both early GATA3 transcription and the early induction of Il4 accessibility. Scientists in the Unit have further demonstrated a critical role for IL-2 in Th2 differentiation both in vitro and in vivo. Their results indicate that IL-2 is essential both for early TCR-mediated IL-4 transcription, for the opening of the Il4 gene and for the maintenance of the gene in an accessible conformation. They have shown that the IL-2 activated factor Stat5 binds to sequences in a region of Dnase I hypersensitivity in the second intron of Il4 gene (HSII) as determined by chromatin immunoprecipitation. Indeed, when active Stat5 is present at high concentrations, Th2 differentiation can be obtained even without the addition of IL-4. Scientists in the Unit have also demonstrated that the probabilistic transcription of IL-4 by Th2 cells is determined by the induction of accessibility at hypersensitivity site VA, a site located 4 kb 3prime of the exon 4. Whereas the accessibility of other portion of the Il4 gene are the same in producers and non-producers, the induced accessibility at VA is 2-3 fold greater among producers. This does not reflect simple differences in strength of signaling since NFAT, a factor that binds to VA, enters the nucleus equally in the Th2 producers and non-producers. Thus the degree of induced accessibility at VA is the stochastic event underlying the probabilistic production of IL-4 by Th2 -differentiated CD4 T cells. These results provide the most detailed picture of the dynamics of Th2-mediated differentiation and of the molecular mechanisms underlying commitment to the capacity to produce IL-4.
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