Enforced Expression of GATA-3 During T Cell Development Inhibits Maturation of CD8 Single-Positive Cells and Induces Thymic Lymphoma in Transgenic Mice

Nawijn, Martijn C.; Ferreira, Rita; Dingjan, Gemma M.; Kahre, Olev; Drabek, Dubravka; Karis, Alar; Grosveld, Frank; Hendriks, Rudolf W.

doi:10.4049/jimmunol.167.2.715

Cited by 83 publications

(81 citation statements)

References 73 publications

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“…We have previously shown that enforced expression of GATA3 in transgenic mice, driven by the CD2 gene promoter and locus control region, inhibited maturation of CD8 SP cells, enhanced Th2 cell development in the periphery and induced thymic lymphoma in aging mice [6,12]. We also identified a small increase in DP cell size and TCRab/CD3 expression levels in CD69 + DP cells, suggesting that enforced GATA3 expression may influence the kinetics of positive selection.…”

Section: Introductionmentioning

confidence: 79%

“…We previously observed that enforced GATA3 expression inhibited maturation of CD8 cells, but did not appear to affect the CD4 versus CD8 lineage fate decision [6]. However, in the CD2-GATA3 transgenic mice analyzed, differences in levels of endogenous GATA3 between developing CD4 and CD8 cells were maintained.…”

Section: Enforced Gata3 Expression Does Not Affect Cd4/ Cd8 Lineage Cmentioning

confidence: 87%

“…S2), showing that in this respect the CD2-GATA3 transgene could functionally replace the endogenous Gata3 gene. Similar to the CD2-GATA3 transgenic mice [6], also the CD2-GATA3 transgenic CD4-Cre Gata3 f/f mice showed defective maturation of CD8 cells, characterized by reduced numbers of CD8 SP cells (Supporting Information Fig. S2), impaired down-regulation of CD69, HSA and CD44, and reduced numbers of splenic CD8 + T cells (data not shown), similar to the phenotype described for CD2-GATA3 transgenic mice on the FVB/N background [6].…”

Section: Enforced Gata3 Expression Does Not Affect Cd4/ Cd8 Lineage Cmentioning

confidence: 97%

“…Similar to the CD2-GATA3 transgenic mice [6], also the CD2-GATA3 transgenic CD4-Cre Gata3 f/f mice showed defective maturation of CD8 cells, characterized by reduced numbers of CD8 SP cells (Supporting Information Fig. S2), impaired down-regulation of CD69, HSA and CD44, and reduced numbers of splenic CD8 + T cells (data not shown), similar to the phenotype described for CD2-GATA3 transgenic mice on the FVB/N background [6]. In spite of this defective CD8 maturation, quantification of thymocyte subpopulations showed that in the absence of differential GATA3 expression between MHC class I-and MHC class II-mediated positive selection both CD4 and CD8 SP cell populations could develop (see Supporting Information Fig.…”

Section: Enforced Gata3 Expression Does Not Affect Cd4/ Cd8 Lineage Cmentioning

confidence: 97%

“…Low lacZ expression was found in DP and CD8 SP thymocytes, whereas high lacZ expression was found in the transitional CD4 hi CD8 lo population and in CD4 SP cells [5,6]. Importantly, RT-PCR and Western blotting experiments demonstrated that GATA3 is up-regulated in response to TCR stimulation during positive selection of CD4 but not CD8 thymocytes [7].…”

Section: Introductionmentioning

confidence: 95%

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GATA3 controls the expression of CD5 and the T cell receptor during CD4 T cell lineage development

et al. 2007

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The transcription factor GATA3 is essential at multiple stages of T cell development, including the earliest double-negative stages, b-selection and CD4 single-positive thymocytes. Here, we show that in CD2-GATA3 transgenic mice, with enforced GATA3 expression driven by the CD2 promoter, thymocytes have reduced levels of CD5, which is a negative regulator of TCR signaling participating in TCR repertoire fine-tuning. Reduction of CD5 expression was most prominent in CD4 + CD8 + double-positive (DP) cells and was associated with increased levels of the transcription factor E2A. Conversely, GATA3-deficient DP thymocytes showed consistently higher CD5 levels and defective TCR up-regulation during their development towards the CD4 lo CD8 lo subpopulation. CD2-GATA3 transgenic mice carrying the MHC class II-restricted TCR DO11.10 also manifested decreased CD5 levels. As in these TCR-transgenic mice reduced CD5 expression cannot result from an effect of GATA3 on repertoire selection, we conclude that enforced GATA3 interferes with the developmentally regulated increase of CD5 levels. Enforced GATA3 expression in DO11.10 transgenic mice was also accompanied by enhanced TCR expression during CD4 positive selection. Because GATA3 is induced by TCR signaling in DP thymocytes, our findings indicate that GATA3 establishes a positive feedback loop that increases TCR surface expression in developing CD4 lineage cells.

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Section: Introductionmentioning

confidence: 79%

Section: Enforced Gata3 Expression Does Not Affect Cd4/ Cd8 Lineage Cmentioning

confidence: 87%

Section: Enforced Gata3 Expression Does Not Affect Cd4/ Cd8 Lineage Cmentioning

confidence: 97%

Section: Enforced Gata3 Expression Does Not Affect Cd4/ Cd8 Lineage Cmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 95%

See 3 more Smart Citations

GATA3 controls the expression of CD5 and the T cell receptor during CD4 T cell lineage development

et al. 2007

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GATA‐3 protects against severe joint inflammation and bone erosion and reduces differentiation of Th17 cells during experimental arthritis

Hamburg

Mus

Bruijn

et al. 2009

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis is associated with the infiltration of T helper cells into the joints. It is unclear whether interferon-␥ (IFN␥)-producing Th1cells or the novel T helper subset, interleukin-17 (IL-17)-producing Th17 cells, are the pathogenic mediators of joint inflammation in chronic nonautoimmune arthritis. Therefore, this study was aimed at examining whether the Th2-specific transcription factor GATA-3 can regulate arthritis, in an experimental murine model, by modulating Th1 and/or Th17 cell polarization.Methods. Arthritis was induced with methylated bovine serum albumin (mBSA) in both wild-type and CD2 T cell-specific GATA-3 (CD2-GATA-3)-transgenic mice. At days 1 and 7 after the induction of arthritis, knee joints were scored macroscopically for arthritis severity and for histologic changes. Single-cell suspensions were generated from the spleens, lymph nodes, and inflamed knee joints. Cytokine expression by CD4؉ T cells was determined using flow cytometry, and IL-17 expression in the inflamed knee joints was determined by enzyme-linked immunosorbent assay. Analyses of gene expression were performed for Th17-associated factors.Results. Wild-type mice developed severe joint inflammation, including massive inflammatory cell infiltration and bone erosion that increased significantly over time, reaching maximal arthritis scores at day 7. In contrast, only mild joint inflammation was observed in CD2-GATA-3-transgenic mice. This mild effect was further accompanied by systemic and local reductions in the numbers of IL-17؉IFN␥؊ and IL-17؉IFN␥؉, but not IL-17؊IFN␥؉, CD4؉ T cells, and by induction of Th2 cytokine expression. Moreover, GATA-3 overexpression resulted in reduced gene expression of the Th17-associated transcription factor retinoic acidrelated orphan receptor ␥t.Conclusion. These results indicate that enforced GATA-3 expression protects against severe joint inflammation and bone erosion in mice, accompanied by reduced differentiation of Th17 cells, but not Th1 cells, during mBSA-induced arthritis.

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Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism

Yao

Uddin

Manley

et al. 2022

Cell Biochemistry & Function

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Gene and protein expression of BTBR T+ Itpr3tf/J (BTBR) mice with autistic‐like behaviours were compared with the C57BL/6J strain, which is considered to have normal immunity and behaviour. Notch signalling pathway was constitutively activated in the immune system and liver of BTBR T+ Itpr3tf/J (BTBR) mice. Notch ligand 4 (Dll4), Notch receptors (Notch1 Notch2 and Notch3) and recombination signal binding protein for immunoglobulin κ j region (RBPJ) were increased both at gene and protein levels in BTBR spleens and thymi. Notch downstream transcriptional factors, Tbx21, Gata3, Rorc and FoxP3 were increased in BTBR spleens, Gata3 and FoxP3 were increased in BTBR thymi and BTBR mice have a high blood CD4/CD8 T cell ratio. Reduced nucleotide excision repair ability in BTBR spleens was associated with increased 8‐oxoguanine, Ogg1 inhibition, an enhanced level of apoptotic thymocytes and higher expression of GATA‐3. Ogg1 inhibition and enhanced GATA‐3 expression also were detected in BTBR brain. Notch signal promoted mitochondrial dynamics switching to enhanced fission with an increased number and mass of mitochondria in immune cells of BTBR mice, but not in livers and brains. Constitutive influences on mitochondria exist in this mouse model of autism spectrum disorder; similar outcomes from environmental exposures might occur perinatally in susceptible individuals to affect the development of autism.

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Enforced Expression of GATA-3 During T Cell Development Inhibits Maturation of CD8 Single-Positive Cells and Induces Thymic Lymphoma in Transgenic Mice

Cited by 83 publications

References 73 publications

GATA3 controls the expression of CD5 and the T cell receptor during CD4 T cell lineage development

GATA3 controls the expression of CD5 and the T cell receptor during CD4 T cell lineage development

GATA‐3 protects against severe joint inflammation and bone erosion and reduces differentiation of Th17 cells during experimental arthritis

Constitutive activation of Notch signalling and T cell activation characterize a mouse model of autism

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