Interleukin-4 is a prototypic type I cytokine that is a central regulator of allergic inflammatory responses. It controls 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, we have identified a Stat6-inducible transcription factor, GFI-1, that when expressed in TH2 cells results in resistance to apoptosis and strikingly enhances cellular proliferation, implying that it is responsible for the increased cell yield seen during IL-4 stimulation. Utilizing mice in which the gene for the green fluorescence protein (GFP) has replaced the first exon of the IL-4 gene, it has been shown that the process of commitment to IL-4 production is a multistep process. In the first step, both IL-4 alleles are rapidly made accessible so that all cells subjected to short-term TH2 priming acquire the ability to produce IL-4, although at a low probability; so that most cytokine positive cells express only a single IL-4 allele (monoallelism). This initial differentiation event is followed by less frequent events that may render one or both the IL-4 alleles more likely to be transcribed and creates an epigenetic allelic preference that is most easily observed in cell clones. We have now shown that differences in degree of IL-4 or GFP production by TH2 clones are linked to variable degrees of chromatin accessibility as shown by CpG methylation and by histone acetylation. We argue that this type of regulation is most efficient for molecules that act in the context of cell/cell interactions and that control threshold-type activities. Important progress has also been made in understanding the dynamics of TH1 CD4 memory T cells. Highly polarized, resting memory cells are transiently activated as a result of in vivo challenge and then eliminated. Finally, we have developed a series of T lymphomas from the cells of a T cell receptor transgenic mouse. These lymphomas have arisen in mice that were stimulated by antigen. These lymphomas appeared in a 3 to 12 month period after immune challenge. These tumors should provide critical insight into the process of lymphomagenesis and should also allow us to characterize specific T cell populations in great depth.
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