The IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, we discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. We reported in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in our lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. We also previously characterized genes that were induced or repressed by IL-2, IL-4, IL-7, and IL-15, including showing the negative regulation of the IL-7 receptor alpha chain, a finding with implications in understanding how IL-2 can promote cell death, and the positive regulation of a dual specificity phosphatase, DUSP5, that negatively regulates IL-2-mediated activation of ERK kinases. T helper cell differentiation is an important process in the regulation of host defense. Th1 differentiation is important for host defense to viruses and other intracelllular pathogens, Th2 differentiation is vital in allergic disorders and related to helminths, and Th17 differentiation is vital in a range of inflammatory disorders, including psoriasis and inflammatory bowel disease, and we previously showed that IL-2 importantly regulates expression of the IL-4 receptor and critically controls priming of cells for Th2 differentiation. During the current period we made the major discovery that IL-2 critically regulates expression of the IL-12Rbeta2 chain, which is a critical component of the IL-12 receptor. We showed that IL-12Rbeta expression is diminished in IL-2 deficient mice and that its expression is induced by IL-2. Consistent with the critical role of IL-12 for Th1 differentiation, we found that IL-2 was required for this process as well, presumably in order to induced IL-12Rbeta expression on the cell surface. Indeed, we found that retroviral transduction of an Il12rb2 retrovirus could rescue defective Th1 differentiation in IL-2 deficient T cells. We also found that IL-2 induced expression of the T-box family transcription factor, T-bet, which is encoded by the Tbx21 gene, although retroviral transduction of Tbx21, unlike Il12rb2, could not restore Th1 differentation. We also demonstrated that IL-2 repressed expression of the IL-6 receptor and gp130, which together mediate responsiveness to IL-6, a cytokine whose signal is required for Th17 differentiation. This is consistent with prior observations that IL-2 inhibits Th17 differentiation. Interestingly, Tbx21 is also an inhibitor of Th17 differentiation, so our demonstration that IL-2 induces Tbx21 provides a second explanation for Th17 inhibition by IL-2. Overall, our data reveal that IL-2 is a potent modulator of Th differentiation, priming for Th1 and Th2 differentiation by inducing expression of IL-4Ralapha and IL-12Rbeta2, while inhbiting Th17 differentiation via its induction of Tbx21 and its inhibition of IL-6 signaling. We also began a study with Dr. Chris Garcia at Stanford, studying the actions of wild type IL-2 versus novel IL-2 variants, a project with potential clinical ramifications. These studies will in part use the pmel-1 T cell receptor transgenic model of adoptive immunotherapy, in collaboration with Dr. Nicholas Restifo, NCI, in terms of the ability to kill tumors. We previously showed that a dual specificity phosphatase, denoted DUSP5, is induced by IL-2 and thus is an IL-2 target gene, and we demonstrated that transgenic overexpression of DUSP5 results in a block in thymocyte development at the CD4/CD8 double positive stage, indicating a role for ERK kinases in this process. We have continued work on this and another related important phosphatase. We also previously demonstrated that there was a critical role for RSk2 in T cell activation and that RSK1 and RSK2 were activated by IL-2 and IL-15 but not IL-7. This past year, we collaborated with Dr. Kang in a study that revealed that RSK2 is essential for FLT3-ITD but is dispensable for BCR-ABL induced myeloid leukemia, a study that indicates the oncogenic potential of this kinase. We also reported the generation of IL-2/IL-21 dual reporter BAC transgenic mice. These mice allow one to observed through surrogate fluorescent markers the relative induction of these cytokines in different cells. Using these mice, we demonstrated used a model mouse system for experimental autoimmune uveitis. We demonstrated the existence of IL-2, IL-21, and IL-2/IL-21 double expressing cells in the retina, consistent with a role for this cytokine in the disease process. Overall, these studies help to improve our understanding of signaling by gc family cytokines. These findings clarify basic molecular mechanisms that are relevant to normal and pathological immune cell function such as allergy, autoimmunity, and cancer.

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2011
Total Cost
$834,964
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
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Xin, Annie; Masson, Frederick; Liao, Yang et al. (2016) A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nat Immunol 17:422-32
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
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Liao, Wei; Spolski, Rosanne; Li, Peng et al. (2014) Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc Natl Acad Sci U S A 111:3508-13
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Ring, Aaron M; Lin, Jian-Xin; Feng, Dan et al. (2012) Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat Immunol 13:1187-95
Lin, Jian-Xin; Li, Peng; Liu, Delong et al. (2012) Critical Role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. Immunity 36:586-99

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