? Interleukin-4 is a prototypic type I cytokine that is the 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 shown that activation of the latent transcription factor, Stat 6, controls both TH2 polarization and IgE class switching. In addition, IL-4-mediated Stat6 signaling rescues activated naive CD4 T cells from apoptosis. Scientists in the Unit have established that both GATA3 and Stat5 are essential for acquisition of IL-4 producing capacity. It has now been shown that activation of the erk signaling pathway prevents transcription of GATA3 and desensitizes the IL-2 receptor. Since both GATA3 and IL-2/ STat5 are essential for early transcription of IL-4, which in turn controls TH2 differentiation, erk activation prevents Th2 commitment. It has been shown that high concentrations of antigen strongly stimulate erk phosphorylation, thereby preventing TH2 differentiation while low concentrations of antigen, which activate erk only weakly, are permissive for early IL-4 production and TH2 differentiation. Utilizing conditional GATA3 knockout mice prepared by scientists in the Unit, it has been shown that GATA3 is essential for priming for IL-4-production both in vitro and in vivo but that cells that have already differentiated into Th2 cells can sustain their IL-4 producing capacity even when GATA3 is eliminated. By contrast, both IL-5 and IL-13 production are strictly dependent on GATA3. ? It has been further demonstrated that GATA3 is a potent growth regulator of TH2 cells and that GATA3 and Gfi-1 act together to induce this striking stimulation of TH2 cell growth. Indeed, Gfi-1 conditional knockout mice show a major diminution in Th2 responses in S. mansoni infections due to diminished growth of these cells. Gfi-1, in its role as a transcriptional repressor, is critical for robust growth to IL-2, since it appears to repress expression of genes such as SOCS1 and SOCS3 that inhbit IL-2 mediated growth. On the other hand, Gfi-1 diminishes growth in response to IL-7 since it is required for TCR- and cytokine-mediated down regulation of the IL-7R alpha chain. These studies, utilizing Gfi-1 conditional knockout mice developed in the Unit, establish that Gfi-1 plays a critical role in lymphocyte homeostasis and that precise regulation of Gfi-1 expression is central to a balanced population of CD4 and CD8 T cells.? P38 has now been shown to play a major role in IL-4 expression. It function is mediated, at least in part, through its regulation of IL-4 mRNA half-life. Th2 cells in which P38 has been activated display long IL-4 mRNA half-lives but if P38 fails to activated or if its activity is blocked, most IL-4 mRNA has been degraded within 30 minutes. Unit scientists have shown that recently activated Th2 cells robustly activate P38 in response to stimulation but that resting memory cells show poor activation, suggesting that effector cells have a striking advantage in the capacity to produce IL-4, at least in part due to their capacity to sustain IL-4 mRNA.? Laboratory scientists have also demonstrated that the transcription of the two alleles at the Il4 locus is governed stochastically and that the likelihood of transcription is associated with the degree of chromatin accessibility of the two alleles. Furthermore, although there are shared requirements for the transcription of IL-4 and IL-13, in individual cells and individual clones, the expression of these cytokines is independently determined. To study this in greater detail, scientists in the Cytokine Biology Unit are using the techniques of recombineering to develop mice that bear fluorescent protein reporters for expression of IL-4, IL-13 and IL-5. In addition, an in depth effort to understand the distinctive signaling mechanisms used for IL-4 and IL-13 responses, with emphasis on the differential roles of the type I and type II IL-4 receptors and how different cell types show very different relative sensitvity to these congeners. For this purpose, responses of various macrophage populations from wild-type and gamma common-deficient mice to IL-4 and IL-13 have been analyzed in detail. The induction of arginase-1, a gene that is rapidly induced through the IL-4 receptor, has been evaluated. An interesting but engimatic finding is that bone marrow derived macrophage populations from gamma common deficient mice respond well to IL-13 but poorly to IL-4 while peritoneal macrophage from the same donors respond well to both IL-4 and IL-13. This model promises to give important insight into the regulation of IL-4 receptor mediated signaling.? LI scientists have also developed new insights into the production of IL-4 by basophils. They have shown that these cells are massively recruited into the tissues, spleen and blood in helminth infection and that this recruitment is T cell dependent. IL-3 appears to play a major role in basophil recruitment. ? Efforts are now underway to use a retroviral cDNA library expression system to identify new genes that play an important role in Th2 priming and maintenance.
| Dewas, Cedric; Chen, Xi; Honda, Tetsuya et al. (2015) TSLP expression: analysis with a ZsGreen TSLP reporter mouse. J Immunol 194:1372-80 |
| Paul, William E (2014) Endless fascination. Annu Rev Immunol 32:1-24 |
| Ben-Sasson, S Z; Wang, K; Cohen, J et al. (2013) IL-1? strikingly enhances antigen-driven CD4 and CD8 T-cell responses. Cold Spring Harb Symp Quant Biol 78:117-24 |
| Paul, William E; Milner, Joshua D; Grossman, Zvi (2013) Pathogen-sensing, regulatory T cells, and responsiveness-tuning collectively regulate foreign- and self-antigen mediated T-cell responses. Cold Spring Harb Symp Quant Biol 78:265-76 |
| van Panhuys, Nicholas; Prout, Melanie; Forbes, Elizabeth et al. (2011) Basophils are the major producers of IL-4 during primary helminth infection. J Immunol 186:2719-28 |
| 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 |
| Zhu, Jinfang; Davidson, Todd S; Wei, Gang et al. (2009) Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells. J Exp Med 206:329-41 |
| 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 |
| 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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