Cynthia Watson
National Institutes of Health
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Featured researches published by Cynthia Watson.
Nature Immunology | 2000
Masaki Terabe; So Matsui; Nancy Noben-Trauth; Hangjiong Chen; Cynthia Watson; Debra D. Donaldson; David P. Carbone; William E. Paul; Jay A. Berzofsky
Using a mouse model in which tumors show a growth-regression-recurrence pattern, we investigated the mechanisms for down-regulation of cytotoxic T lymphocyte–mediated tumor immuno-surveillance. We found that interleukin 4 receptor (IL-4R) knockout and downstream signal transducer and activator of transcription 6 (STAT6) knockout, but not IL-4 knockout, mice resisted tumor recurrence, which implicated IL-13, the only other cytokine that uses the IL-4R–STAT6 pathway. We confirmed this by IL-13 inhibitor (sIL-13Rα2–Fc) treatment. Loss of natural killer T cells (NKT cells) in CD1 knockout mice resulted in decreased IL-13 production and resistance to recurrence. Thus, NKT cells and IL-13, possibly produced by NKT cells and signaling through the IL-4R–STAT6 pathway, are necessary for down-regulation of tumor immunosurveillance. IL-13 inhibitors may prove to be a useful tool in cancer immunotherapy.
Nature Immunology | 2004
Booki Min; Jane Hu-Li; Cynthia Watson; Alex Grinberg; Qi Wang; Nigel Killeen; Joseph F. Urban; Liying Guo; William E. Paul
Expression of the transcription factor GATA-3 is strongly associated with T helper type 2 (TH2) differentiation, but genetic evidence for its involvement in this process has been lacking. Here, we generated a conditional GATA-3-deficient mouse line. In vitro deletion of Gata3 diminished both interleukin 4 (IL-4)–dependent and IL-4-independent TH2 cell differentiation; without GATA-3, TH1 differentiation occurred in the absence of IL-12 and interferon-γ. Gata3 deletion limited the growth of TH2 cells but not TH1 cells. Deletion of Gata3 from established TH2 cells abolished IL-5 and IL-13 but not IL-4 production. In vivo deletion of Gata3 using OX40-Cre eliminated TH2 responses and allowed the development of interferon-γ-producing cells in mice infected with Nippostrongylus brasiliensis. Thus, GATA-3 serves as a principal switch in determining TH1-TH2 responses.
Science | 1995
Tomohiro Yoshimoto; Albert Bendelac; Cynthia Watson; Jane Hu-Li; William E. Paul
Immune responses dominated by interleukin-4 (IL-4)-producing T helper type 2 (TH2) cells or by interferon γ (IFN-γ)-producing T helper type 1 (TH1) cells express distinctive protection against infection with different pathogens. Interleukin-4 promotes the differentiation of naïve CD4+ T cells into IL-4 producers and suppresses their development into IFN-γ producers. CD1-specific splenic CD4+NK1.1+ T cells, a numerically minor population, produced IL-4 promptly on in vivo stimulation. This T cell population was essential for the induction of IL-4-producing cells and for switching to immunoglobulin E, an IL-4-dependent event, in response to injection of antibodies to immunoglobulin D.
Nature | 2000
Masaki Terabe; So Matsui; Nancy Noben-Trauth; Hangjiong Chen; Cynthia Watson; Debra D. Donaldson; David P. Carbone; William E. Paul; Jay A. Berzofsky
Using a mouse model in which tumors show a growth-regression-recurrence pattern, we investigated the mechanisms for down-regulation of cytotoxic T lymphocyte–mediated tumor immuno-surveillance. We found that interleukin 4 receptor (IL-4R) knockout and downstream signal transducer and activator of transcription 6 (STAT6) knockout, but not IL-4 knockout, mice resisted tumor recurrence, which implicated IL-13, the only other cytokine that uses the IL-4R–STAT6 pathway. We confirmed this by IL-13 inhibitor (sIL-13Rα2–Fc) treatment. Loss of natural killer T cells (NKT cells) in CD1 knockout mice resulted in decreased IL-13 production and resistance to recurrence. Thus, NKT cells and IL-13, possibly produced by NKT cells and signaling through the IL-4R–STAT6 pathway, are necessary for down-regulation of tumor immunosurveillance. IL-13 inhibitors may prove to be a useful tool in cancer immunotherapy.
Cell | 1987
Melissa A. Brown; Jacalyn H. Pierce; Cynthia Watson; Joseph Falco; James N. Ihle; William E. Paul
BSF-1/interleukin-4, a product of activated T cells, has multiple biological activities that affect cells of most hematopoietic lineages. Among these is the ability of BSF-1 to costimulate the growth of mast cells and regulate the production of IgE. We demonstrate here that BSF-1 mRNA is expressed by a majority of transformed mast cell lines and by 5 IL-3-dependent non-transformed mast cell lines. BSF-1 activity, including the ability to enhance the growth of IL-3-dependent mast cells, was detected in the supernatants of transformed mast cells. The role of BSF-1 as a mast cell growth factor, its constitutive production by transformed mast cells, and the lack of IL-3 production by most of these cells raise the possibility that BSF-1 may act as an autocrine growth factor for some transformed mast cells. Furthermore, production of BSF-1 mRNA by nontransformed cells indicates that mast cells may be an important physiologic source of this factor.
Journal of Immunology | 2001
Liying Guo; Cynthia Watson; Jane Hu-Li; William E. Paul
IL-4 plays a critical role in the differentiation of TCR-stimulated naive CD4 T cells to the Th2 phenotype. In response to IL-4, the IL-4R activates a set of phosphotyrosine binding domain-containing proteins, including insulin receptor substrate 1/2, Shc, and IL-4R interacting protein, as well as Stat6. Stat6 has been shown to be required for Th2 differentiation. To determine the roles of the phosphotyrosine binding adaptors in Th2 differentiation, we prepared a retrovirus containing a mutant of the human (h)IL-4R α-chain, Y497F, which is unable to recruit these adaptors. The mutant hIL-4Rα, as well as the wild-type (WT) hIL-4Rα, was introduced into naive CD4 T cells. Upon hIL-4 stimulation, Y497F worked as well as the WT hIL-4Rα in driving Th2 differentiation, as measured by Gata3 up-regulation and IL-4 production. Furthermore, IL-4-driven cell expansion was also normal in the cells infected with Y497F, although cells infected with Y497F were not capable of phosphorylating insulin receptor substrate 2. These results suggest that the signal pathway mediated by Y497 is dispensable for both IL-4-driven Th2 differentiation and cell expansion. Both WT and Y497F hIL-4Rα lose the ability to drive Th2 differentiation and cell expansion in Stat6-knockout CD4 T cells. A constitutively activated form of Stat6 introduced into CD4 T cells resulted in both Th2 differentiation and enhanced cell expansion. Thus, activated Stat6 is necessary and sufficient to mediate both IL-4-driven Th2 differentiation and cell expansion in CD4 T cells.
Immunity | 2002
Liying Guo; Booki Min; Cynthia Watson; Jane Hu-Li; Howard A Young; Philip N. Tsichlis; William E. Paul
IL-4 is important in Th2 differentiation and in cell expansion. Stat6 is necessary and sufficient for both functions. Although Gata3 is critical for Th2 polarization, it is not sufficient to mediate IL-4-driven cell expansion. We report that growth factor independent-1 (Gfi-1), a Stat6-dependent transcriptional repressor, strikingly increases Th2 cell expansion by promoting proliferation and preventing apoptosis. Cells infected with a Gfi-1 retrovirus show striking enhancement of IL-2-induced Stat5 phosphorylation and repression of p27(Kip-1) expression, suggesting a potential mechanism for the Gfi-1 growth effect. The synergy of Gfi-1 and Gata3 provides a mechanism through which IL-4 could selectively promote Th2 cell expansion.
Immunity | 2001
Jane Hu-Li; Christophe Pannetier; Liying Guo; Max Löhning; Hua Gu; Cynthia Watson; Mario Assenmacher; Andreas Radbruch; William E. Paul
CD4 cells from mice heterozygous for an IL-4 and a GFP/IL-4 gene frequently express a single allele. Analysis of IL-4 or GFP production by cells from recently primed Th2 cells indicates that essentially all are competent to transcribe either allele but have a low probability of doing so. By contrast, long-term Th2 clones show distinct and heritable ratios in the proportion of cells that express IL-4 or GFP. We conclude that in the course of Th2 priming an early efficient event renders both alleles capable of being inefficiently transcribed; a second, less frequent event occurs that renders one allele more competent, accounting for the differential expression of IL-4 and GFP in different clones.
Proceedings of the National Academy of Sciences of the United States of America | 2002
Liying Guo; Jane Hu-Li; Cynthia Watson; Michael J. Difilippantonio; Christophe Pannetier; William E. Paul
TH2 clones may produce very variable amounts of IL-4. Among six TH2 clones prepared from homozygous or heterozygous mice in which Gfp replaced the first exon of Il4, a range of patterns of CpG methylation in the Il4/Il13 locus was observed correlating with the degree of expression of IL-4 or green fluorescence protein. Patterns of histone acetylation also showed differences between “high” and “low” TH2 clones. These results indicate that in TH2 cells the Il4 locus may display variable patterns of chromatin accessibility associated with distinct degrees of IL-4 expression. This finding suggests a regulation of IL-4 expression keyed to the function of this cytokine in cell/cell interactions and in the regulation of threshold responses.
The Journal of Allergy and Clinical Immunology | 2013
Ilkka Junttila; Cynthia Watson; Laura Kummola; Xi Chen; Jane Hu-Li; Liying Guo; Ryoji Yagi; William E. Paul
BACKGROUND IL-13 is a critical effector cytokine for allergic inflammation. It is produced by several cell types, including mast cells, basophils, and TH2 cells. In mast cells and basophils its induction can be stimulated by cross-linkage of immunoglobulin receptors or cytokines. The IL-1 family members IL-33 and IL-18 have been linked to induction of IL-13 production by mast cells and basophils. In CD4 TH2 cells IL-33-mediated production of IL-13 requires simultaneous signal transducer and activator of transcription (STAT) 5 activation. OBJECTIVE Here we have addressed whether cytokine-induced IL-13 production in mast cells and basophils follows the same logic as in TH2 cells: requirement of 2 separate signals. METHODS By generating a bacterial artificial chromosome (BAC) transgenic IL-13 reporter mouse, we measured IL-13 production in mast cells and basophils. RESULTS In mast cells harvested from peritoneal cavities, 2 cytokine signals are required for IL-13 production: IL-33 and IL-3. In bone marrow mast cells IL-13 production requires IL-33, but the requirement for a STAT5 inducer is difficult to evaluate because these cells require the continuous presence of IL-3 (a STAT5 activator) for survival. Poorer STAT5 inducers in culture (IL-4 or stem cell factor) result in less IL-13 production on IL-33 challenge, but the addition of exogenous IL-3 enhances IL-13 production. This implies that bone marrow-derived mast cells, like peritoneal mast cells and TH2 cells, require stimulation both by an IL-1 family member and a STAT5 inducer to secrete IL-13. Basophils follow the same rule; splenic basophils produce IL-13 in response to IL-18 or IL-33 plus IL-3. CONCLUSION Optimal IL-13 production from mast cells and basophils requires 2 cytokine signals.