Interleukin (IL-) 4 plays critical roles in immune responses. The differentiation of effector T cell function is especially important, along with the pro-survival and mitogenic effects of IL-4, can determine susceptibility to allergic, infectious and autoimmune diseases. Our long-term goal is to understand the molecular mechanisms of IL-4 signal transduction and regulation of gene transcription in lymphoid cells, especially primary cells and in the intact animal. A key strategy is to understand the role of signaling motifs in the IL-4R alpha (IL-4R?) chain in these processes. Work using tissue culture cell lines with IL-4 as the only stimulus led to a basic model of how the IL-4 receptor works. In the preceding cycle of support, we uncovered important evidence of mechanisms which do not fit within the conventional model. A unifying theme of these discoveries is that Stat transcription factor induction and the primary structural basis of IL-4R? function are different in the activated T lymphocyte from what has been observed in 'resting'tissue culture cell lines. IL-4 induced Stat5 in a process blocked by an inhibitor of NF-KB transcription factors, and IL-4R? chains lacking all cytoplasmic tyrosines were competent to lead to State activation and Th2 differentiation. The central hypothesis of this proposal is that the IL-4R complex undergoes functional changes in the activated lymphocyte, which we term """"""""reprogramming"""""""", and that these changes are important in terms of receptor function in the intact animal.
In Aim 1, we will characterize the role of molecules and signaling pathways important for altering the functional programming of IL-4R? induction of Stat proteins. We will test whether or not a common set of signal transduction pathways recruited after T cell activation endows this cytokine receptor with each of its altered functional characteristics.
In Aim 2, we will investigate mechanisms of IL-4- induced proliferation of normal T cells, including the role of an """"""""ID-1 region"""""""" that was required for State induction by """"""""tyrosine-free"""""""" IL-4R?.
In Aim 3, we plan to determine the functional impact of this new State induction pathway in a Th2 response in vivo. The proposed studies are significant at several levels. At a biochemical level, independent of function in vivo, they address a question of general and fundamental significance about the rules which govern how selectivity is achieved by cytokine receptors in activating specific Stat transcription factors. Second, they suggest that a functionally important form of cross-talk influences the functions of IL-4 (and perhaps also IL-13) during immune responses. Taken together, the experiments of these Specific Aims will provide new insights into the regulation of T cell proliferation, Th2 responses, and allergic disease pathophysiology. Lay Language Summary: The receptor for interleukin 4, IL-4R?, is the main signal relay leading to allergic diseases and asthma. Based on evidence suggesting new ways in which IL-4R? works in one particular type of white blood cell, the T lymphocyte, we propose to identify new mechanisms of interleukin 4 signaling. Success in this research could lead to new therapeutic strategies in allergic diseases or asthma.
|Lee, Keunwook; Nam, Ki Taek; Cho, Sung Hoon et al. (2012) Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J Exp Med 209:713-28|
|Cho, Sung Hoon; Ahn, Annie K; Bhargava, Prerna et al. (2011) Glycolytic rate and lymphomagenesis depend on PARP14, an ADP ribosyltransferase of the B aggressive lymphoma (BAL) family. Proc Natl Acad Sci U S A 108:15972-7|
|Gordy, Laura E; Bezbradica, Jelena S; Flyak, Andrew I et al. (2011) IL-15 regulates homeostasis and terminal maturation of NKT cells. J Immunol 187:6335-45|
|Dunaway, Charlene M; Hwang, Yoonha; Lindsley, Craig W et al. (2011) Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis. Mol Cell Biol 31:404-16|
|Lee, Keunwook; Gudapati, Prathyusha; Dragovic, Srdjan et al. (2010) Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32:743-53|
|Cho, Sung Hoon; Goenka, Shreevrat; Henttinen, Tiina et al. (2009) PARP-14, a member of the B aggressive lymphoma family, transduces survival signals in primary B cells. Blood 113:2416-25|
|Adeeku, Eric; Gudapati, Prathyusha; Mendez-Fernandez, Yanice et al. (2008) Flexibility accompanies commitment of memory CD4 lymphocytes derived from IL-4 locus-activated precursors. Proc Natl Acad Sci U S A 105:9307-12|