The interleukin-2 receptor and related cytokine/cytokine receptor systems are being studied to understand critical components of the T cell immune response in normal and neoplastic cells. Following T-cell activation, IL-2 and IL-2 receptors are induced;the magnitude and duration of the T-cell immune response is controlled by the amount of IL-2 produced, the levels of receptors expressed, and the time course of these events. Expression of IL-2Ra is interestingly high in cells infected with HTLV-I, the cause of adult T cell leukemia (ATL) and tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). Three chains of the IL-2 receptor exist, IL-2Ra, IL-2Rb, and gc, with IL-2Ra and IL-2Rb being significantly regulated at the level of transcription. gc is a shared chain also used by the receptors for IL-4, IL-7, IL-9, IL-15, and IL-21, and is the protein that is mutated in XSCID. We have focused primarily on the types of signals induced by some of these cytokines, particularly the activation of STAT proteins (signal transducers and activators of transcription), and the mechanism by which they regulate cytokine/STAT target genes. Given our prior observations that STAT5A or STAT5B transgenic mice develop tumors, which was consistent with STAT5 being implicated in malignant transformation and elevated in a range of human tumors, this is an important area for both normal and pathological states. T helper cell differentiation is important in the regulation of host defense, with Th1 differentiation being important for host defense to viruses and other intracelllular pathogens, Th2 differentiation being vital in allergic disorders and related to helminths, and Th17 differentiation being vital in a range of inflammatory disorders, including psoriasis and inflammatory bowel disease. We previously demonstrated that IL-2 plays an important role for Th2 differentiation and reported that IL-2 importantly regulates expression of the IL-4 receptor in a STAT5-dependent manner and critically controls priming of cells for Th2 differentiation. Moreover, using genome-wide Solexa-based ChIP-Seq analysis (a methodology combining chromatin immunoprecipitation with DNA sequencing), we had discovered that there is broad regulation of Th2 differentiation via STAT5 proteins, with both STAT5A and STAT5B being important. Moreover, IL-2-mediated IL-4Ra induction is a key step in priming cells for Th2 differentiation. Unexpectedly, whereas IL-4 can also upregulate IL-4Ra expression, T-cell receptor-mediated IL-4Ra induction is dependent on IL-2 rather than IL-4. These findings provided novel insights into the mechanism of priming for Th2 differentiation. We substantially extended these findings by showing that IL-2 via STAT5 induces expression of IL-12Rb1 and IL-12Rb2 and that the induction of IL-12Rb2 in particular is critical for the induction of responsiveness to IL-12 and thereby Th1 differentiation. We defined a critical GAS motif for the regulation of IL-12Rb2. In addition, we showed that IL-2 via STAT5 also regulates the T box protein, T-bet. Interestingly, in contrast to the induction of IL-12R proteins, IL-2 inhibits expression of IL-6Ra and gp130, helping to explain the inhibition of Th17 differentiation. Consistent with the ability of Tbx21 to inhibit Th17 differentiation, expression of Tbx21 in Th17 cells resulted in increased IFNg but decreased expression of IL-17A. These results indicate a very broad effect of IL-2 via STAT5 on T helper cell differentation. We have also continued more detailed basic studies of STAT proteins, including the importance of STAT tetramerization for gene regulation and to elucidate more about the role of STAT proteins in Adult T cell leukemia. We also demonstrated that STAT mediates TSLP-induced survival and proliferation of CD4+ T cells. Overall, the above findings enhance our understanding of mechanisms by which the gc family of cytokines control gene expression to regulate the immune response.

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Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2011
Total Cost
$1,252,446
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
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DUNS #
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Lin, Jian-Xin; Leonard, Warren J (2018) The Common Cytokine Receptor ? Chain Family of Cytokines. Cold Spring Harb Perspect Biol 10:
Spolski, Rosanne; Li, Peng; Leonard, Warren J (2018) Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol :
Mitra, Suman; Leonard, Warren J (2018) Biology of IL-2 and its therapeutic modulation: Mechanisms and strategies. J Leukoc Biol 103:643-655
Shin, Hyun Mu; Kapoor, Varun N; Kim, Gwanghun et al. (2017) Transient expression of ZBTB32 in anti-viral CD8+ T cells limits the magnitude of the effector response and the generation of memory. PLoS Pathog 13:e1006544
Oh, Jangsuk; Wang, Yujuan; Chen, Shida et al. (2017) Genetic background-dependent role of Egr1 for eyelid development. Proc Natl Acad Sci U S A 114:E7131-E7139
Spolski, Rosanne; Gromer, Daniel; Leonard, Warren J (2017) The ? c family of cytokines: fine-tuning signals from IL-2 and IL-21 in the regulation of the immune response. F1000Res 6:1872
Li, Peng; Mitra, Suman; Spolski, Rosanne et al. (2017) STAT5-mediated chromatin interactions in superenhancers activate IL-2 highly inducible genes: Functional dissection of the Il2ra gene locus. Proc Natl Acad Sci U S A 114:12111-12119
Lin, Jian-Xin; Du, Ning; Li, Peng et al. (2017) Critical functions for STAT5 tetramers in the maturation and survival of natural killer cells. Nat Commun 8:1320
Sathyanarayana, Bangalore K; Li, Peng; Lin, Jian-Xin et al. (2016) Molecular Models of STAT5A Tetramers Complexed to DNA Predict Relative Genome-Wide Frequencies of the Spacing between the Two Dimer Binding Motifs of the Tetramer Binding Sites. PLoS One 11:e0160339
Yan, Ming; Wang, Hongsheng; Sun, Jiafang et al. (2016) Cutting Edge: Expression of IRF8 in Gastric Epithelial Cells Confers Protective Innate Immunity against Helicobacter pylori Infection. J Immunol 196:1999-2003

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