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 showed that the Stat6-inducible transcription factor, GFI-1 when expressed in TH2 cells, allows prolonged signaling through the IL-2 receptor and thus allows a striking growth advantage of cells expressing both Gfi-1 and Gata3, providing insight into the mechanism through which TH2 cells may come to dominate lymphocyte populations. Scientists in the Unit have also demonstrated that the IL-4 gene may exist in a series of distinct accessibility states in TH2 cells and that the probability that IL-4 will be transcribed by a given TH2 cells is dependent upon the degree of accessibility. This probabilistic expression explains monoallelism at the IL-4 locus and provides a system in which the proportion of homogeneously differentiated cells that actually produce IL-4 varies depending upon the state of chromatin. Important progress has also been made in understanding the dynamics of CD4 T cells in neonatal mice. Scientists in the Unit have demonstrated that the first cohort of CD4 T cells exiting from the thymus encounters a lymphopenic environment. A sub-population of cells within this cohort is stimulated to divide multiple times over a relatively short period and to differentiate into cells with a memory phenotype. The division of these cells is dependent upon T cell receptor mediated recognition and is independent of IL-7. Despite the finding that only some of the cells respond and that their response is TCR dependent, the repertoire of the responding cells is very broad, as shown by an analysis of TCR-Vbeta distribution and of CDR3 lengths among cells expressing a given Vbeta. The physiologic significance of the rapid development of a pool of highly diverse memory cells in neonatal mice is under active investigation. have A series of more than 15 T lymphomas have been obtained from the cells of a T cell receptor transgenic mouse. These lymphomas have arisen in mice that were stimulated by antigen. The lymphomas appeared in a 3 to 12 month period after immune challenge. The tumors show recurrent patterns of gene expression; they tend to over-express both Gata3 and Gfi-1; with one exception, they have down-regulated CD4 expression. They provide a system through which the steps in antigen-driven lymphomagenesis can be traced and the key genetic factors analyzed.
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| Ben-Sasson, Shlomo Z; Hu-Li, Jane; Quiel, Juan et al. (2009) IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci U S A 106:7119-24 |
| Guo, Liying; Wei, Gang; Zhu, Jinfang et al. (2009) IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci U S A 106:13463-8 |
| Milner, Joshua D; Brenchley, Jason M; Laurence, Arian et al. (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:773-6 |
| Min, Booki; Paul, William E (2008) Basophils and type 2 immunity. Curr Opin Hematol 15:59-63 |
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