Inhibition of Th1 Development Mediated by GATA-3 through an IL-4-Independent Mechanism

Ouyang, Wenjun; Ranganath, Sheila; Weindel, Kathryn; Bhattacharya, Deepta; Murphy, Theresa L.; Sha, William C.; Murphy, Kenneth M.

doi:10.1016/s1074-7613(00)80671-8

Cited by 714 publications

(690 citation statements)

References 56 publications

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“…It has been suggested that cytokines and their receptors, transcription factors, MHC determinants, Ag peptides, and costimulatory signals are important for Th1 and Th2 cell differentiation 1 2 3 4 5 6 7 8 9. However, to date, the precise mechanism responsible for the differentiation and development of polarized Th1 responses has not been fully clarified in humans.…”

mentioning

confidence: 99%

Txk, a Nonreceptor Tyrosine Kinase of the Tec Family, Is Expressed in T Helper Type 1 Cells and Regulates Interferon γ Production in Human T Lymphocytes

Kashiwakura

Suzuki

Nagafuchi

et al. 1999

The Journal of Experimental Medicine

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Differentiation of human T cells into T helper (Th)1 and Th2 cells is vital for the development of cell-mediated and humoral immunity, respectively. However, the precise mechanism responsible for the Th1 cell differentiation is not fully clarified. We have studied the expression and function of Txk, a member of the Tec family of nonreceptor tyrosine kinases. We found that Txk expression is restricted to Th1/Th0 cells with IFN-γ producing potential. Txk transfection of Jurkat T cells resulted in a several-fold increase of IFN-γ mRNA expression and protein production; interleukin (IL)-2 and IL-4 production were unaffected. Antisense oligodeoxynucleotide of Txk specifically inhibited IFN-γ production of normal peripheral blood lymphocytes, antigen-specific Th1 clones, and Th0 clones; IL-2 and IL-4 production by the T cells was unaffected. Txk cotransfection led to the enhanced luciferase activity of plasmid (p)IFN-γ promoter/enhancer (pIFN-γ[-538])-luciferase–transfected Jurkat cells upon mitogen activation. Txk transfection did not affect IL-2 and IL-4 promoter activities. Thus, Txk specifically upregulates IFN-γ gene transcription. In fact, Txk translocated from cytoplasm into nuclei upon activation and transfection with a mutant Txk expression plasmid that lacked a nuclear localization signal sequence did not enhance IFN-γ production by the cells, indicating that nuclear localization of Txk is obligatory for the enhanced IFN-γ production. In addition, IL-12 treatment of peripheral blood CD4+ T cells enhanced the Txk expression, whereas IL-4 treatment completely inhibited it. These results indicate that Txk expression is intimately associated with development of Th1/Th0 cells and is significantly involved in the IFN-γ production by the cells through Th1 cell–specific positive transcriptional regulation of the IFN-γ gene.

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mentioning

confidence: 99%

Txk, a Nonreceptor Tyrosine Kinase of the Tec Family, Is Expressed in T Helper Type 1 Cells and Regulates Interferon γ Production in Human T Lymphocytes

Kashiwakura

Suzuki

Nagafuchi

et al. 1999

The Journal of Experimental Medicine

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“…The MSCV-based bi-cistronic retroviral vector is a commonly used system for ectopic expression of cDNA [33][34][35][36], in which surface expression of the marker protein not only correlates with the successful expression of the gene of interest [37], but also enables to identify and isolate individual, successfully transduced T lymphocytes according to the expression of human CD4 (hCD4) (Fig. 1A, right).…”

Section: Generation and Retroviral Expression Of Shp-2 Isoforms In Prmentioning

confidence: 99%

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

Hoff

Brunner‐Weinzierl

2007

Eur J Immunol

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Although phosphatases are key players of intracellular processes, not much is known about the phosphatase SHP-2 during T cell differentiation. Here we show that ectopic over-expression of SHP-2 in primary T helper cells directly reduced the frequency of individual lymphocytes expressing pro-inflammatory cytokines after antigen-specific stimulation by a mechanism impairing activation of protein kinase C. In addition we demonstrate that SHP-2 mediates enhanced migration upon CXCR4 signaling in a G-protein-dependent manner. Most strikingly, SHP-2 mediated a dramatic increase in apoptosis by highly enhanced activation of caspases. Co-immunoprecipitations of SHP-2 and c-Cbl from primary T helper cells demonstrated that SHP-2 strongly interacts with the ubiquitin ligase c-Cbl, indicating that c-Cbl could mediate the negative signals of SHP-2. Our results show that SHP-2 signal transduction regulates central checkpoints of T cell differentiation by the activation of distinct signaling cascades.

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“…The expression of these transcription factors is induced as Th precursor cells become Th2 e ectors. Interestingly, the induction of GATA-3 expression in Th2 cells has been shown to be dependent on IL-4 stimulated Stat6 activation, although it is unclear whether or not Stat6 activates GATA-3 transcription directly (Ouyang et al, 1998). Ectopic expression of activated Stat6 in Th1 cells can also result in the expression of GATA-3 and c-maf in these cells (Kurata et al, 1999).…”

Section: Stat6 and T Helper Cell Differentiationmentioning

confidence: 99%

The biology of Stat4 and Stat6

2000

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Inhibition of Th1 Development Mediated by GATA-3 through an IL-4-Independent Mechanism

Cited by 714 publications

References 56 publications

Txk, a Nonreceptor Tyrosine Kinase of the Tec Family, Is Expressed in T Helper Type 1 Cells and Regulates Interferon γ Production in Human T Lymphocytes

Txk, a Nonreceptor Tyrosine Kinase of the Tec Family, Is Expressed in T Helper Type 1 Cells and Regulates Interferon γ Production in Human T Lymphocytes

The tyrosine phosphatase SHP‐2 regulates differentiation and apoptosis of individual primary T lymphocytes

The biology of Stat4 and Stat6

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