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Cited by 393T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisGenomics and Chromatin Dynamics

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Gata-3 Induces T Helper Cell Type 2 (Th2) Cytokine Expression and Chromatin Remodeling in Committed Th1 Cells

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Lee, Hyun Jun, Takemoto, Naofumi, Kurata, Hirokazu, Kamogawa, Yumiko, Miyatake, Shoichiro, O'Garra, Anne, Arai, Naoko·2000·The Journal of Experimental Medicine
DOI 10.1084/jem.192.1.105PMC PMC1887713
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Abstract

Committed T helper type 1 (Th1) and Th2 effector cells, resulting from chronic antigenic stimulation in interleukin (IL)-12 and IL-4, are implicated in the pathology of autoimmune and allergic diseases. Committed Th1 cells cannot be induced to change their cytokine profiles in response to antigenic stimulation and Th2 cytokine–inducing conditions. Here, we report that ectopic expression of GATA-3 induced Th2-specific cytokine expression not only in developing Th1 cells but also in otherwise irreversibly committed Th1 cells and a Th1 clone, HDK1. Moreover, cAMP, an inhibitor of cytokine production by Th1 cells, markedly augmented Th2 cytokine production in GATA-3–expressing Th1 cells. Ectopic expression of GATA-3 in developing Th1 cells, but not in Th1 clone HDK1, induced endogenous GATA-3, suggesting an autoregulatory mechanism for maintenance of GATA-3 expression in Th2 cells. Structure–function analyses of GATA-3 revealed that the NH2-terminal transactivation domain and the COOH-terminal zinc finger domain of GATA-3 were critical, whereas the NH2-terminal zinc finger domain was dispensable for the induction of IL-4. Both zinc fingers, however, were required for IL-5 induction. A Th2-specific DNaseI-hypersensitive site of the IL-4 locus was detected in GATA-3–expressing Th1 cells. Thus, GATA-3 can change the phenotype of committed Th1 cells, previously considered to be irreversible.

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Figure 1 GATA-3 induces IL-4 and IL-5 in developing as well as committed Th1 cells. Naive CD4 T cells from DO11.10 TCR–transgenic mice were stimulated with OVA323–339 and splenic APCs under Th1-polarizing conditions (IL-12 and anti–IL-4). On days 1 and 2 after stimulation, T cells were infected with retroviruses encoding either EGFP (R-EGFP) or GATA-3 bicistronically with EGFP (R-GATA-3-EGFP), and GFP+ populations, EGFP+ or GATA-3+, respectively, were purified by flow cytometry. A portion of noninfected T cells was restimulated on day 7 with Ag and APCs under the Th1 conditions and was infected on days 8 and 9 with retroviruses. For day 22 infection, cells after 3 wk of polarization under Th1-inducing conditions were infected with recombinant retrovirus as above, except that the infection was repeated for three consecutive days. On day 7 after each last stimulation, GFP+ (GATA-3+) or GFP− (GATA-3−) T cells were purified by flow cytometry. A Th1 clone, HDK1, was stimulated with KLH and splenic APCs infected with either R-EGFP or R-GATA-3-EGFP on days 1 and 2. GFP+ cells were purified on day 14 and stimulated with PMA/ionomycin for 48 h, and the level of cytokines in supernatants was determined by immunoassay. 1, 2, and 3 wk polarized Th2 cells produced ∼5, 15–20, or 30–50 ng/ml, respectively. Results were representative of three experiments with similar results.
Figure 1 GATA-3 induces IL-4 and IL-5 in developing as well as committed Th1 cells. Naive CD4 T cells from DO11.10 TCR–transgenic mice were stimulated with OVA323–339 and splenic APCs under Th1-polarizing conditions (IL-12 and anti–IL-4). On days 1 and 2 after stimulation, T cells were infected with retroviruses encoding either EGFP (R-EGFP) or GATA-3 bicistronically with EGFP (R-GATA-3-EGFP), and GFP+ populations, EGFP+ or GATA-3+, respectively, were purified by flow cytometry. A portion of noninfected T cells was restimulated on day 7 with Ag and APCs under the Th1 conditions and was infected on days 8 and 9 with retroviruses. For day 22 infection, cells after 3 wk of polarization under Th1-inducing conditions were infected with recombinant retrovirus as above, except that the infection was repeated for three consecutive days. On day 7 after each last stimulation, GFP+ (GATA-3+) or GFP− (GATA-3−) T cells were purified by flow cytometry. A Th1 clone, HDK1, was stimulated with KLH and splenic APCs infected with either R-EGFP or R-GATA-3-EGFP on days 1 and 2. GFP+ cells were purified on day 14 and stimulated with PMA/ionomycin for 48 h, and the level of cytokines in supernatants was determined by immunoassay. 1, 2, and 3 wk polarized Th2 cells produced ∼5, 15–20, or 30–50 ng/ml, respectively. Results were representative of three experiments with similar results.CC BY-NC-SA · PubMed Central
Figure 3 GATA-3 induces endogenous GATA-3 but not c-maf. RNase protection assay for GATA-3 and c-maf transcripts was performed using total cellular RNAs as described in Materials and Methods. The locations of protected bands for c-maf and for endogenous as well as introduced GATA-3 transcripts are indicated.
Figure 3 GATA-3 induces endogenous GATA-3 but not c-maf. RNase protection assay for GATA-3 and c-maf transcripts was performed using total cellular RNAs as described in Materials and Methods. The locations of protected bands for c-maf and for endogenous as well as introduced GATA-3 transcripts are indicated.CC BY-NC-SA · PubMed Central
Image 5
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Image 9
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Figure 5 GATA-3 and c-maf differentially regulate mouse IL-4 and IL-5 promoter activities. EL-4 cells were cotransfected with 1 μg of reporter construct, pIL-4(−766)Luc 13 or pmIL5Luc(1.2) 42 and the transactivators in the expression vector, either pMEGATA3 25 (0, 1, and 2 μg) or pMEc-maf (0, 1, and 2 μg), by DEAE dextran procedure as described previously 20. Transfection efficiency was monitored using 0.1 μg of pRSV-LacZ. pMEc-maf encoding full-length murine c-maf 40 was cloned by PCR. After 36-h incubation, cells were either unstimulated (open bars) or stimulated (filled bars) for 12 h with PMA (10 ng/ml)/ionomycin (1 μM), and luciferase activity was measured in whole cell extracts and normalized to protein mass as described 65. The data is representative of more than three independent experiments.
Figure 5 GATA-3 and c-maf differentially regulate mouse IL-4 and IL-5 promoter activities. EL-4 cells were cotransfected with 1 μg of reporter construct, pIL-4(−766)Luc 13 or pmIL5Luc(1.2) 42 and the transactivators in the expression vector, either pMEGATA3 25 (0, 1, and 2 μg) or pMEc-maf (0, 1, and 2 μg), by DEAE dextran procedure as described previously 20. Transfection efficiency was monitored using 0.1 μg of pRSV-LacZ. pMEc-maf encoding full-length murine c-maf 40 was cloned by PCR. After 36-h incubation, cells were either unstimulated (open bars) or stimulated (filled bars) for 12 h with PMA (10 ng/ml)/ionomycin (1 μM), and luciferase activity was measured in whole cell extracts and normalized to protein mass as described 65. The data is representative of more than three independent experiments.CC BY-NC-SA · PubMed Central
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Metadata

Authors
Lee, H. J., Takemoto, N., Kurata, H., Kamogawa, Y., Miyatake, S., O'Garra, A., & Arai, N.
Affiliations
  • aDepartment of Immunology, DNAX Research Institute, Palo Alto, California 94304-1104
  • Institute of Medical Science, The University of Tokyo (JP)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2000-07-03
Volume
192
Issue
1
Pages
105-116
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.192.1.105
PMC
PMC1887713
OpenAlex
W2119767265
Cited by
393
References
72
Citations by year
2026: 4 · 2025: 5 · 2024: 8 · 2023: 5 · 2022: 1 · 2021: 9 · 2020: 7 · 2019: 4 · 2018: 11 · 2017: 7 · 2016: 13 · 2015: 8 · 2014: 22 · 2013: 13 · 2012: 9
FWCI
10.63
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
GATA3, Th1 cells, Th2 cytokines, IL-4, IL-5, chromatin remodeling, DNase I hypersensitive sites, cyclic AMP, zinc finger, transactivation domain, T helper cell differentiation, cytokine gene expression
MeSH terms
Animals, Cells, Cultured, Chromatin, DNA-Binding Proteins, Gene Expression Regulation, Genetic Vectors, Interferon-gamma, Mice, Inbred BALB C, Moloney murine leukemia virus, Recombinant Proteins, Transfection, CD4-Positive T-Lymphocytes, Trans-Activators, Interleukin-4, Interleukin-5, Cytokines, Zinc Fingers, Th1 Cells, Th2 Cells, GATA3 Transcription Factor, Mice

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