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  • 1
    Online Resource
    Online Resource
    Rockefeller University Press ; 2007
    In:  The Journal of Experimental Medicine Vol. 204, No. 9 ( 2007-09-03), p. 2145-2157
    In: The Journal of Experimental Medicine, Rockefeller University Press, Vol. 204, No. 9 ( 2007-09-03), p. 2145-2157
    Abstract: Recently, a new developmental pathway for CD4 T cells that is mediated by major histocompatibility complex class II–positive thymocytes was identified (Choi, E.Y., K.C. Jung, H.J. Park, D.H. Chung, J.S. Song, S.D. Yang, E. Simpson, and S.H. Park. 2005. Immunity. 23:387–396; Li, W., M.G. Kim, T.S. Gourley, B.P. McCarthy, D.B. Sant'angelo, and C.H. Chang. 2005. Immunity. 23:375–386). We demonstrate that thymocyte-selected CD4 (T-CD4) T cells can rapidly produce interferon γ and interleukin (IL) 4 upon in vivo and in vitro T cell receptor stimulation. These T-CD4 T cells appear to be effector cells producing both T helper type 1 (Th1) and Th2 cytokines, and they maintain a potential to produce Th2 cytokines under Th1-skewing conditions in a signal transducer and activator of transcription 6–independent manner. The IL-4 mRNA level is high in CD4 single-positive thymocytes if they are selected on thymocytes, which is at least partly caused by enhanced histone acetylation of the IL-4 locus. However, mice that can generate T-CD4 T cells showed attenuated immune responses in an allergen-induced airway inflammation model, suggesting a protective role for T-CD4 T cells during an airway challenge. Our results imply that this thymic selection pathway plays an important role in determining the effector function of the resulting CD4 cells and in regulating immune response.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
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    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2007
    detail.hit.zdb_id: 1477240-1
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  • 2
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2005
    In:  The Journal of Immunology Vol. 174, No. 6 ( 2005-03-15), p. 3440-3446
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 174, No. 6 ( 2005-03-15), p. 3440-3446
    Abstract: Although caspase activation is critical for T cell proliferation following activation, the role of caspases in T cell differentiation is unclear. In this study, we have examined the effect of inhibition of caspases on the process of Th1/Th2 differentiation. Naive CD4+ T cells activated under neutral differentiation conditions in the presence of the pan caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (Z-VAD) fluoromethylketone showed increased Th2 cell differentiation concomitant with an up-regulation of GATA-3. Z-VAD induced optimal Th2 differentiation when T cells were stimulated under strong primary activation conditions. Treatment of naive CD4+ T cells with Z-VAD under strong activation conditions led to a 6-fold increase in IL-4 mRNA compared with control-treated T cells. The Z-VAD-induced increase in IL-4 transcription occurred within 24 h of activation and was independent of Stat6. IFN-γ mRNA expression was not affected by Z-VAD at the 24-h time point. Z-VAD did not augment IL-4 expression from a committed Th2 cell, suggesting that caspases regulate IL-4 expression specifically during primary T cell activation. Z-VAD did not augment IL-12-driven Th1 differentiation. Activation of T cells in the presence of Z-VAD led to a specific increase in the expression of the transcription factor c-fos. Lastly, retrovirus-mediated expression of the antiapoptotic protein Bcl-2 resulted in an enhancement of Th2 cytokine expression, suggesting that inhibition of caspase activation by Bcl-2 can also modulate IL-4 expression. These findings reveal a novel regulatory mechanism of cytokine expression by caspases, and may explain how signaling pathways that inhibit apoptosis tend to promote Th2 differentiation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 184, No. 1_Supplement ( 2010-04-01), p. 141.14-141.14
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 184, No. 1_Supplement ( 2010-04-01), p. 141.14-141.14
    Abstract: The well documented Ets family transcription factor, PU.1 is an important regulator of mast cell, granulocyte and B cell development. Previous studies from our laboratory have identified a novel role for PU.1 in regulating Th2 cell cytokine expression. To further define a role for PU.1 in the development of allergic inflammation in vivo, we studied the development of allergic airway inflammation in mice with a conditional deletion of PU.1 in T cells. Despite the development of normal Th2-responses in the periphery, PU.1 deficient T cells have attenuated allergic inflammation in the lung as compared to wild type mice. To elucidate the mechanism for decreased inflammation in the lung, analysis of cytokines and chemokines from mice that had T cells lacking PU.1, demonstrated significantly decreased levels of IL-9 in the bronchoalveolar lavage fluid concomitant with a significant reduction in the pro-allergic chemokines, CCL17 & CCL22 in lung tissue. We identified PU.1 as a factor that promotes the Th9 phenotype by both repressing Th2 cytokine production and increasing IL-9 production. PU.1 was required for normal generation of IL-9 secreting T cells in vitro and ectopic expression of PU.1 increased IL-9 and chemokine production from Th9 cultures. Together, these data suggest a critical role for PU.1 in generating the Th9 phenotype and in the development of allergic inflammation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 190, No. 1_Supplement ( 2013-05-01), p. 59.13-59.13
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 190, No. 1_Supplement ( 2013-05-01), p. 59.13-59.13
    Abstract: Mast cells are important effectors of innate and adaptive immunity; however their role in atopic dermatitis is not completely understood. Studies from our laboratory have shown that transgenic mice expressing active Stat6 (Stat6VT) in T cells spontaneously develop atopic dermatitis with increased infiltration of eosinophils, lymphocytes and mast cells. Mice with allergic skin inflammation (ASI) also had increased expression of the mast cell growth factor Il9 in the skin. In order to elucidate the role of mast cells in ASI in Stat6VT mice, we generated Stat6VT mice on mast cell deficient background (Stat6VTxB6-KitW-sh/W-sh). Mast cell deficiency in Stat6VT mice did not protect mice from disease and instead led to increased severity and occurrence of symptoms of ASI. To understand the mechanisms of the increased pathogenesis, we defined cytokine production by peripheral T cells and gene expression and histological changes in the skin. Peripheral T cells from mast cell-deficient Stat6VT mice demonstrated increased levels of IL-9, compared to Stat6VT transgenic mice on a wild type background. Further, mast cell deficiency in Stat6VT mice resulted in a substantial decrease in the expression of IL-10 concomitant with increased infiltration of inflammatory cells including eosinophils, lymphocytes and neutrophils. Our results suggest that mast cells provide an immunomodulatory function in Stat6VT mice with ASI.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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  • 5
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 180, No. 5 ( 2008-03-01), p. 3551-3559
    Abstract: IL-4 is required for the pathogenesis of atopic diseases and immune regulation. Stat6 is critical for IL-4-induced gene expression and Th cell differentiation. Recently, we have generated mice expressing a mutant Stat6 (Stat6VT) under control of the CD2 locus control region that is transcriptionally active independent of IL-4 stimulation. To determine whether active Stat6 in T cells is sufficient to alter immune regulation in vivo, we mated Stat6VT transgenic mice to IL-4-deficient mice. Stat6VT expression in IL-4-deficient lymphocytes was sufficient to alter lymphocyte homeostasis and promote Th2 differentiation in vitro. HyperTh2 levels in Stat6 transgenic mice correlated with an atopic phenotype that manifested as blepharitis and pulmonary inflammation with a high level of eosinophilic infiltration. In the absence of endogenous IL-4, Stat6VT transgenic mice were protected from allergic inflammation. Thus, in mice with hyperTh2 immune responses in vivo, IL-4 is a critical effector cytokine.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 190, No. 1_Supplement ( 2013-05-01), p. 50.14-50.14
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 190, No. 1_Supplement ( 2013-05-01), p. 50.14-50.14
    Abstract: Th17 cells are critical for the clearance of extracellular bacteria and fungi, but also contribute to the pathology of autoimmune diseases and asthma. Th17 cells can acquire a Th1-like phenotype in vitro and in vivo, but less is known about their ability to adopt Th2 and Th9 effector programs. To explore this in more detail, we generated an IL-17F lineage tracer mouse strain that allows tracking of cells that formerly expressed IL-17F and can be used to test stability of the Th17 phenotype. Th17 cells cultured under polarizing conditions that promote Th1, Th2 or Th9 differentiation adopt the respective effector programs, expressing lineage associated transcription factors, and secreting IFN-γ, IL-4 or IL-9, while diminishing IL-17 production and expression of RORγt. To explore the stability of Th17 cells in an in vivo environment that is associated with the development of Th2 and Th9 cells, we used the adjuvant-dependent, OVA/Alum and the adjuvant-free, house dust mite models of allergic airway disease (AAD). In both models of AAD, Th17 cells from the lungs of diseased mice did not secrete alternative cytokines nor adopt Th1, Th2 or Th9 effector programs, but remained stable IL-17-secretors. Thus, although Th1-biased pro-inflammatory environments have been shown to induce alternative cytokine expression from Th17 cells in vivo, our data suggest that during allergic inflammatory disease, Th17 cells are remarkably stable, and retain the potential to produce IL-17.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 184, No. 6 ( 2010-03-15), p. 3186-3190
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 184, No. 6 ( 2010-03-15), p. 3186-3190
    Abstract: IL-4 promotes the development of Th2 cells and allergic inflammation. In atopic dermatitis lesions, IL-4 decreases the expression of multiple genes associated with innate defense, including genes in the epidermal differentiation complex (EDC) that regulate epidermal barrier function. However, it is not clear whether IL-4 also contributes to homeostatic control of EDC genes. In this report, we demonstrate that expression of EDC genes and barrier function is increased in the absence of endogenous IL-4. Mice that express a constitutively active Stat6 (Stat6VT) are prone to the development of allergic skin inflammation and have decreased expression of EDC genes. IL-4 deficiency protects Stat6VT transgenic mice from the development of allergic skin inflammation and decreased recovery time in barrier function following skin irritation, with a concomitant increase in EDC gene expression. These data suggest that IL-4 plays an important role in regulating epidermal homeostasis and innate barrier function.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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  • 8
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2005
    In:  The Journal of Immunology Vol. 174, No. 4 ( 2005-02-15), p. 2098-2105
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 174, No. 4 ( 2005-02-15), p. 2098-2105
    Abstract: IL-10 is a key regulatory cytokine produced by T lymphocytes. Although Th2 cells are a major source of IL-10, little is known about IL-10 gene regulation in Th2 cells. High levels of IL-10 mRNA transcription are induced in the Th2 clone D10 after PMA plus ionomycin (P/I) stimulation; however we found that the IL-10 promoter was not inducible by P/I in D10 cells. We therefore sought regulatory regions in the IL-10 gene that could promote P/I-activated transcription in Th2 cells. Two strong DNase I-hypersensitive sites (DHSSs) were identified in the IL-10 gene in mouse T cells, and conserved noncoding sequences (CNSs) between the mouse and human IL-10 genes were also identified. One IL-10 DHSS maps within or next to a highly conserved CNS region, CNS-3. The CNS-3 region contains an AP-1 site that binds JunB and c-Jun proteins specifically in Th2 cells and not in Th1 cells. The CNS-3 element activates transcription from the IL-10 promoter after P/I stimulation and is responsive to c-Jun and JunB. Retroviral mediated-expression of either c-Jun or JunB in primary T cells led to a large increase in IL-10 expression, and inhibition of AP-1 activity by a dominant negative form of c-Jun in primary T cells strongly repressed IL-10 expression. IFN-γ was relatively unaffected by modulations in AP-1 activity. These data indicate that we have identified a novel regulatory element that can specifically activate transcription of the IL-10 gene in Th2 cells via the AP-1/Jun pathway.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
    detail.hit.zdb_id: 1475085-5
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  • 9
    Online Resource
    Online Resource
    American Thoracic Society ; 2003
    In:  American Journal of Respiratory Cell and Molecular Biology Vol. 29, No. 5 ( 2003-11), p. 634-641
    In: American Journal of Respiratory Cell and Molecular Biology, American Thoracic Society, Vol. 29, No. 5 ( 2003-11), p. 634-641
    Type of Medium: Online Resource
    ISSN: 1044-1549 , 1535-4989
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    Language: English
    Publisher: American Thoracic Society
    Publication Date: 2003
    detail.hit.zdb_id: 1473629-9
    SSG: 12
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  • 10
    In: Immunity, Elsevier BV, Vol. 29, No. 5 ( 2008-11), p. 679-690
    Type of Medium: Online Resource
    ISSN: 1074-7613
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 2001966-X
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