GATA-3 Suppresses Th1 Development by Downregulation of Stat4 and Not through Effects on IL-12Rβ2 Chain or T-bet

Usui, Takashi; Nishikomori, Ryuta; Kitani, Atsushi; Strober, Warren

doi:10.1016/s1074-7613(03)00057-8

Cited by 239 publications

(239 citation statements)

References 36 publications

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“…The cells with decoupled proliferation and effector cytokine response show increased expression of GATA-3. Overexpression of GATA-3 alters the relative expression between T-bet and GATA-3 and perhaps suppresses cytokine production by decoupled HA-specific CD4 + T cells, in ways similar to the known suppression of IFN-g production in T-bet-expressing CD4 + T cells by GATA-3 overexpression (24,25). However, the reason for suppression of IL-4 production in GATA-3-overexpressing decoupled HA-specific CD4 + T cells is not clear.…”

Section: Discussionmentioning

confidence: 89%

Altered T-bet Dominance in IFN-γ–Decoupled CD4+ T Cells with Attenuated Cytokine Storm and Preserved Memory in Influenza

Dutta

Miaw

et al. 2013

The Journal of Immunology

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Cytokine storm has been postulated as one of the major causes of mortality in patients with severe respiratory viral infections such as influenza. With the help of an influenza Ag- specific mouse experimental system, we report that CD4+ T cells contribute effector cytokines leading to lung inflammation in acute influenza. Although virus can no longer be detected from tissues 14 d postinfection, virus-derived Ag continues to drive a CD4+ T cell response after viral clearance. Ag-specific CD4+ T cells proliferate and evolve into memory CD4+ T cells efficiently, but the production of effector cytokines is seriously hampered during this phase. This decoupling of proliferation and effector cytokine production doesn’t appear in conjunction with increased suppression by regulatory T cells or decreased induction of transcription factors. Rather, GATA-3 and ROR-γt levels are elevated when compared with cells that have effector cytokine production. T-bet dominance over GATA-3 and ROR-γt decreases with the disarmament of effector cytokine production. Importantly, upon reinfection, these decoupled cells produce elevated levels of IFN-γ and were effective in virus eradication. These results provide a mechanism through altered T-bet dominance to dampen the cytokine storm without impeding the generation of memory T cells in influenza virus infection.

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Section: Discussionmentioning

confidence: 89%

Altered T-bet Dominance in IFN-γ–Decoupled CD4+ T Cells with Attenuated Cytokine Storm and Preserved Memory in Influenza

Dutta

Miaw

et al. 2013

The Journal of Immunology

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“…Th1/Th17 cells are characterized by the coexpression of the cytokines IFN-g and IL-17 and the lineage-defining and -determining transcription The differentiation and maintenance of Th lineage phenotypes, in particular their memory for cytokine expression has been intensely studied [26,27]. Several mechanisms have been identified, such as the inhibition of the Th2 master transcription factor GATA-3 through T-bet-mediated phosphorylation [28], the GATA-3-mediated downregulation of the IL-12Rb2 chain [29] or STAT4 [30], or the sequestering of cytokine genes into heterochromatin [31], which restrict the plasticity of differentiated Th lineage cells. This has led to the overall picture that once fully differentiated cells of the various Th lineages are committed and resistant to conversion into other lineages [32].…”

Section: Discussionmentioning

confidence: 99%

“…Several mechanisms have been identified, such as the inhibition of the Th2 master transcription factor GATA-3 through T-bet-mediated phosphorylation [28], the GATA-3-mediated downregulation of the IL-12Rb2 chain [29] or STAT4 [30], or the sequestering of cytokine genes into heterochromatin [31], which restrict the plasticity of differentiated Th lineage cells. This has led to the overall picture that once fully differentiated cells of the various Th lineages are committed and resistant to conversion into other lineages [32].…”

Section: Discussionmentioning

confidence: 99%

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

et al. 2010

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Th1 and Th17 cells are distinct lineages of effector/memory cells, imprinted for reexpression of , by upregulated expression of T-bet and retinoic acid-related orphan receptor ct (RORct) , respectively. Apparently, Th1 and Th17 cells share tasks in the control of inflammatory immune responses. Th cells coexpressing IFN-c and IL-17 have been observed in vivo, but it remained elusive, how these cells had been generated and whether they represent a distinct lineage of Th differentiation. It has been shown that ex vivo isolated Th1 and Th17 cells are not interconvertable by TGF-b/IL-6 and IL-12, respectively. Here, we show that ex vivo isolated Th17 cells can be converted into Th1/Th17 cells by combined IFN-c and IL-12 signaling. IFN-c is required to upregulate expression of the IL-12Rb2 chain, and IL-12 for Th1 polarization. These Th1/Th17 cells stably coexpress RORct and T-bet at the single-cell level. Our results suggest a molecular pathway for the generation of Th1/Th17 cells in vivo, which combine the pro-inflammatory potential of Th1 and Th17 cells. IntroductionTh1 cells, with a memory for IFN-g expression and determined by the master transcription factor T-bet, are considered to be essential for protection against intracellular pathogens, and had been viewed as the major pathogenic drivers of chronic autoimmune inflammation, e.g. EAE [1][2][3], uveitis [4] or colitis [5]. Recently, Th17 cells, with a memory for expression of IL-17 and determined by the transcription factor retinoic acid related orphan receptor gt (RORgt), have been identified as another pathogenic Th-cell lineage driving pathogenesis in these autoimmune models [6,7]. Th17 cells contribute to inflammation through the recruitment of neutrophils and the induction of secretion of pro-inflammatory mediators such as IL-6, IL-8, TNF-a, IL-1b, CXCL1, CXCL10 and matrix metalloproteinases from tissue cells (reviewed in [8]). Th1 cells contribute to inflammation by activation of macrophages [9]. The concerted action of IFN-g and IL-17 has been shown to be essential in the effective induction and maintenance of autoimmunity [10,11], e.g. Th1 cells being required for the recruitment of Th17 cells into the central nervous system in EAE.In inflamed tissue of autoimmune patients, Th cells coexpressing IFN-g and IL-17 have been identified [12][13][14].Ã These authors have contributed equally to this study. ResultsIn vivo, Th17 cells do not express IL-12Rb2 and do not respond to IL-12Although IL-17-expressing cells isolated from cultures stimulated in vitro respond to subsequent stimulation with IL-12 with gain of IFN-g expression and loss of IL-17 expression (Fig. 1A, upper panel), IL-17 expressing cells directly isolated ex vivo maintained IL-17 expression and could not be induced to express IFN-g in the presence of IL-12 (Fig. 1A, lower panel) [17,19]. To identify the molecular mechanism of refraction of in vivo generated Th17 cells to conversion by IL-12, we here compared the expression of genes relevant for IL-12 signaling by Th17 cells generated in vit...

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“…It has been argued that the main role of T-bet is to negatively regulate GATA-3 function, rather than to positively regulate the IFN-␥ gene (32). Such inhibition was proposed to relieve the inhibition of STAT4 imposed by GATA-3 in Th2 cells (33). STAT4 signaling induced by IL-12 would then induce the production of IFN-␥.…”

Section: Discussionmentioning

confidence: 99%

Temporal Dissection of T-bet Functions

Matsuda

George²,

Hagman

et al. 2007

The Journal of Immunology

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T-bet is a transcription factor of the T-box family that regulates the expression of numerous immune system-associated genes. T-bet directs the acquisition of the Th1-associated genetic program in differentiating CD4+ lymphocytes. It also influences the development of NK and NKT cells through its regulation of the IL-2/IL-15Rβ-chain (CD122) and the trafficking of these lymphocytes through CxCR3. The temporal requirements of T-bet activity for the production of IFN-γ and the regulation of CD122 and CxCR3 expression remain undefined. We produced an ectopically controllable form of T-bet by fusing its C-terminal domain with a mutated ligand-binding domain of human estrogen receptor α. By temporally controlling the expression of T-bet-estrogen receptor α by the addition or removal of 4-hydroxytamoxifen (4-HT), we show that IFN-γ, CD122, and CxCR3 are direct gene targets of T-bet whose expression are acutely regulated by T-bet activity.

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GATA-3 Suppresses Th1 Development by Downregulation of Stat4 and Not through Effects on IL-12Rβ2 Chain or T-bet

Cited by 239 publications

References 36 publications

Altered T-bet Dominance in IFN-γ–Decoupled CD4+ T Cells with Attenuated Cytokine Storm and Preserved Memory in Influenza

Altered T-bet Dominance in IFN-γ–Decoupled CD4+ T Cells with Attenuated Cytokine Storm and Preserved Memory in Influenza

IFN‐γ and IL‐12 synergize to convert in vivo generated Th17 into Th1/Th17 cells

Temporal Dissection of T-bet Functions

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