scholarly journals Signal Transducer and Activator of Transcription 6 Controls Chemokine Production and T Helper Cell Type 2 Cell Trafficking in Allergic Pulmonary Inflammation

2001 ◽  
Vol 193 (9) ◽  
pp. 1087-1096 ◽  
Author(s):  
Anuja Mathew ◽  
James A. MacLean ◽  
Elliot DeHaan ◽  
Andrew M. Tager ◽  
Francis H.Y. Green ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Effector Function ◽  
Th2 Cells ◽  
Cell Trafficking ◽  
Signal Transducer ◽  
T Helper ◽  
Chemokine Production ◽  
Th2 Cell

Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotal role in the induction of allergic asthma, but the mechanisms regulating their recruitment into the airways are unknown. Signal transducer and activator of transcription factor (Stat)6 is a transcription factor essential for Th2 cell differentiation. Here we show that Stat6 also controls Th2 cell recruitment and effector function in allergic inflammation in vivo. To isolate the role of Stat6 in regulating Th2 cell trafficking and effector function from its role in Th2 cell differentiation, we used a murine model of asthma in which in vitro–differentiated Stat6+/+ antigen-specific Th2 cells were adoptively transferred into naive Stat6−/− and Stat6+/+ mice followed by aerosol antigen challenge. We found that all of the features of asthma, including Th2 cell accumulation, Th2 and eosinophil-active chemokine production, and airway eosinophilia, mucus production, and hyperresponsiveness seen in Stat6+/+ mice, were dramatically absent in Stat6−/− mice that received Stat6+/+ antigen-specific Th2 cells. Our findings establish Stat6 as essential for Th2 cell trafficking and effector function and suggest that interruption of Stat6 signaling in resident cells of the lung is a novel approach to asthma therapy.

scholarly journals Bcl11b, a novel GATA3-interacting protein, suppresses Th1 while limiting Th2 cell differentiation

2018 ◽  
Vol 215 (5) ◽  
pp. 1449-1462 ◽  
Author(s):  
Difeng Fang ◽  
Kairong Cui ◽  
Gangqing Hu ◽  
Rama Krishna Gurram ◽  
Chao Zhong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Differentiation ◽  
Epigenetic Modification ◽  
B Cell Lymphoma ◽  
Regulatory Elements ◽  
Th2 Cells ◽  
Th2 Cell

GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein–protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5, and IL-13, is up-regulated in Bcl11b-deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated genes (from RNA sequencing), cobinding patterns (from chromatin immunoprecipitation sequencing), and Bcl11b-modulated epigenetic modification and gene accessibility suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.

scholarly journals Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level.

1996 ◽  
Vol 184 (2) ◽  
pp. 473-483 ◽  
Author(s):  
T Sornasse ◽  
P V Larenas ◽  
K A Davis ◽  
J E de Vries ◽  
H Yssel
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Biological Activities ◽  
Th2 Cells ◽  
Cell Phenotype ◽  
T Helper ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Th1 And Th2

The development of CD4+ T helper (Th) type 1 and 2 cells is essential for the eradication of pathogens, but can also be responsible for various pathological disorders. Therefore, modulation of Th cell differentiation may have clinical utility in the treatment of human disease. Here, we show that interleukin (IL) 12 and IL-4 directly induce human neonatal CD4- T cells, activated via CD3 and CD28, to differentiate into Th1 and Th2 subsets. In contrast, IL-13, which shares many biological activities with IL-4, failed to induce T cell differentiation, consistent with the observation that human T cells do not express IL-13 receptors. Both the IL-12-induced Th1 subset and the IL-4-induced Th2 subset produce large quantities of IL-10, confirming that human IL-10 is not a typical human Th2 cytokine. Interestingly, IL-4-driven Th2 cell differentiation was completely prevented by an IL-4 mutant protein (IL-4.Y124D), indicating that this molecule acts as a strong IL-4 receptor antagonist. Analysis of single T cells producing interferon gamma or IL-4 revealed that induction of Th1 cell differentiation occurred rapidly and required only 4 d of priming of the neonatal CD4+ T cells in the presence of IL-12. The IL-12-induced Th1 cell phenotype was stable and was not significantly affected when repeatedly stimulated in the presence of recombinant IL-4. In contrast, the differentiation of Th2 cells occurred slowly and required not only 6 d of priming, but also additional restimulation of the primed CD4+ T cells in the presence of IL-4. Moreover, IL-4-induced Th2 cell phenotypes were not stable and could rapidly be reverted into a population predominantly containing Th0 and Th1 cells, after a single restimulation in the presence of IL-12. The observed differences in stability of IL-12- and IL-4-induced human Th1 and Th2 subsets, respectively, may have implications for cytokine-based therapies of chronic disease.

scholarly journals Critical Involvement of CD44 in T Helper Type 2 Cell-Mediated Eosinophilic Airway Inflammation in a Mouse Model of Acute Asthma

2022 ◽  
Vol 12 ◽  
Author(s):  
Shigeki Katoh
Keyword(s):  
Monoclonal Antibodies ◽  
Airway Inflammation ◽  
Th17 Cells ◽  
Acute Asthma ◽  
Mite Allergen ◽  
Th2 Cells ◽  
T Helper ◽  
Th2 Cell ◽  
Helper Type

Interactions between CD44 and hyaluronan (HA) are crucial for recruiting leukocytes to inflamed tissues. This review summarizes findings from our studies of the roles of CD44-HA interactions in leukocyte trafficking, with a particular focus on airway T helper type 2 (Th2) cells in mouse models of acute asthma. In a mite allergen-induced model of acute asthma, intraperitoneal injection of anti-CD44 monoclonal antibodies blocked lymphocytes and eosinophils from accumulating in the lung, and suppressed both the antigen-induced increase in Th2 cytokines in the bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness (AHR). CD44 deficiency was associated with decreased mite allergen-induced Th2 cell-mediated airway inflammation and AHR in sensitized mice. Asthmatic responses to antigen-sensitized splenic CD4+ T cells transferred from CD44-deficient mice were weaker than in wild-type mice. Administration of anti-CD44 monoclonal antibodies preferentially suppressed the airway accumulation of antigen-specific Th2 cells induced by antigen challenge, without affecting Th1 and Th17 cells. Increased HA-binding ability of CD44 and expression of Neu1 sialidase were observed on antigen-specific Th2 cells compared with antigen-specific Th1 and Th17 cells. Finally, in a mouse model of acute asthma, neuraminidase 1-deficient SM/J mice exhibited a lower Th2 cytokine concentration and a lower absolute Th2 cell number in the BALF, as well as an attenuated AHR. Our findings indicate that CD44 critically contributes to the antigen challenge-induced airway accumulation of antigen-specific Th2 cells, without affecting Th1 and Th17 cells, in mice. Furthermore, neuraminidase 1 activity is necessary for the interaction between HA and CD44, and Th2 cell-mediated airway inflammation.

scholarly journals Understanding the Generation and Regulation of IL-4 Producing T Helper 2 Cells

2021 ◽  
Author(s):  
◽  
Helen Mearns
Keyword(s):  
Cell Activity ◽  
Physiological Role ◽  
Th2 Cells ◽  
Total Serum ◽  
T Helper ◽  
Th2 Response ◽  
Th2 Cell ◽  
Reporter Mice

<p>A keenly sought therapeutic approach for the treatment of allergic disease is the identification and neutralization of the cytokine that regulates the differentiation of Th2 cells. Th2 cells are CD4 T cells differentiated to secrete IL-4. These cells are exciting new targets for asthma therapies due to the key role they play in allergic airway diseases. Recently the cytokine IL-25 has been shown to enhance Th2 cell activity and play important roles in mediating allergic inflammatory responses. To investigate this further we crossed IL-25 deficient mice with GFP-IL-4 reporter mice and developed an assay of in vitro and in vivo IL-4 independent Th2 differentiation. These assays were used to determine whether IL-25 was critical for the formation of Th2 cells. We found there was no physiological role for IL-25 in either the differentiation of Th2 cells or their development to effector or memory Th2 subsets. In the strong Th2 setting of a helminth infection the absence of IL-25 resulted in no defects in the effector type 2 responses associated with T helper type 2 immunity including, mucous hyperplasia, class switching to IgE and protection against challenge infections. Importantly this data challenges the newly found and growing status of the cytokine IL-25 and its proposed role in promoting Th2 responses. The second part of this thesis investigated whether the genomic organisation, which reflects commitment to Th2 cytokine expression, could provide a clearer definition of a functional in vivo Th2 cell. Two distinct IL-4 reporter mice were crossed and Th2 in vivo assays were developed that allowed tracking of the individual alleles of IL-4 in a variety of tissue types and Th2 subsets. Interestingly in vivo expression of IL-4 is mostly monoallelic yet there is a small highly activated population of biallelic IL-4 expressing Th2 cells. Physiologically each allele of IL-4 was required for a functional Th2 response with total serum IgE titres up to 4 fold lower in IL-4+/- heterozygous compared to the IL-4+/+ sufficient animals and a significant loss in protective immunity against challenge infections with helminths occurred in the IL-4+/- heterozygous animals. The similarity in deficiencies in Th2 immunity in the IL-4+/- heterozygous and IL-4-/- deficient compared to the IL-4+/+ sufficient animals lead to the proposal that the generation of biallelic Th2 cells may be required for specialised cell-to-cell mediated delivery of tailored activation signals and higher quantities of IL-4 required to mediate fully developed Th2 immune responses.</p>

scholarly journals SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1443-1453 ◽  
Author(s):  
Helena Ahlfors ◽  
Amita Limaye ◽  
Laura L. Elo ◽  
Soile Tuomela ◽  
Mithila Burute ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Target Genes ◽  
Cell Polarization ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Th2 Cell ◽  
Th Cell ◽  
Gata3 Expression ◽  
Direct Binding

Abstract Special AT-rich binding protein 1 (SATB1) is a global chromatin organizer and a transcription factor regulated by interleukin-4 (IL-4) during the early T helper 2 (Th2) cell differentiation. Here we show that SATB1 controls multiple IL-4 target genes involved in human Th cell polarization or function. Among the genes regulated by SATB1 is that encoding the cytokine IL-5, which is predominantly produced by Th2 cells and plays a key role in the development of eosinophilia in asthma. We demonstrate that, during the early Th2 cell differentiation, IL-5 expression is repressed through direct binding of SATB1 to the IL-5 promoter. Furthermore, SATB1 knockdown-induced up-regulation of IL-5 is partly counteracted by down-regulating GATA3 expression using RNAi in polarizing Th2 cells. Our results suggest that a competitive mechanism involving SATB1 and GATA3 regulates IL-5 transcription, and provide new mechanistic insights into the stringent regulation of IL-5 expression during human Th2 cell differentiation.

scholarly journals Pyrrothiogatain acts as an inhibitor of GATA family proteins and inhibits Th2 cell differentiation in vitro

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shunsuke Nomura ◽  
Hirotaka Takahashi ◽  
Junpei Suzuki ◽  
Makoto Kuwahara ◽  
Masakatsu Yamashita ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Dna Binding ◽  
Binding Activity ◽  
Th2 Cells ◽  
Th2 Cytokines ◽  
Screening System ◽  
Dna Binding Activity ◽  
Th2 Cell ◽  
Gata Family

AbstractThe transcription factor GATA3 is a master regulator that modulates T helper 2 (Th2) cell differentiation and induces expression of Th2 cytokines, such as IL-4, IL-5, and IL-13. Th2 cytokines are involved in the protective immune response against foreign pathogens, such as parasites. However, excessive production of Th2 cytokines results in type-2 allergic inflammation. Therefore, the application of a GATA3 inhibitor provides a new therapeutic strategy to regulate Th2 cytokine production. Here, we established a novel high-throughput screening system for an inhibitor of a DNA-binding protein, such as a transcription factor, and identified pyrrothiogatain as a novel inhibitor of GATA3 DNA-binding activity. Pyrrothiogatain inhibited the DNA-binding activity of GATA3 and other members of the GATA family. Pyrrothiogatain also inhibited the interaction between GATA3 and SOX4, suggesting that it interacts with the DNA-binding region of GATA3. Furthermore, pyrrothiogatain significantly suppressed Th2 cell differentiation, without impairing Th1 cell differentiation, and inhibited the expression and production of Th2 cytokines. Our results suggest that pyrrothiogatain regulates the differentiation and function of Th2 cells via inhibition of GATA3 DNA binding activity, which demonstrates the efficiency of our drug screening system for the development of novel small compounds that inhibit the DNA-binding activity of transcription factors.

scholarly journals Understanding the Generation and Regulation of IL-4 Producing T Helper 2 Cells

2021 ◽  
Author(s):  
◽  
Helen Mearns
Keyword(s):  
Cell Activity ◽  
Physiological Role ◽  
Th2 Cells ◽  
Total Serum ◽  
T Helper ◽  
Th2 Response ◽  
Th2 Cell ◽  
Reporter Mice

<p>A keenly sought therapeutic approach for the treatment of allergic disease is the identification and neutralization of the cytokine that regulates the differentiation of Th2 cells. Th2 cells are CD4 T cells differentiated to secrete IL-4. These cells are exciting new targets for asthma therapies due to the key role they play in allergic airway diseases. Recently the cytokine IL-25 has been shown to enhance Th2 cell activity and play important roles in mediating allergic inflammatory responses. To investigate this further we crossed IL-25 deficient mice with GFP-IL-4 reporter mice and developed an assay of in vitro and in vivo IL-4 independent Th2 differentiation. These assays were used to determine whether IL-25 was critical for the formation of Th2 cells. We found there was no physiological role for IL-25 in either the differentiation of Th2 cells or their development to effector or memory Th2 subsets. In the strong Th2 setting of a helminth infection the absence of IL-25 resulted in no defects in the effector type 2 responses associated with T helper type 2 immunity including, mucous hyperplasia, class switching to IgE and protection against challenge infections. Importantly this data challenges the newly found and growing status of the cytokine IL-25 and its proposed role in promoting Th2 responses. The second part of this thesis investigated whether the genomic organisation, which reflects commitment to Th2 cytokine expression, could provide a clearer definition of a functional in vivo Th2 cell. Two distinct IL-4 reporter mice were crossed and Th2 in vivo assays were developed that allowed tracking of the individual alleles of IL-4 in a variety of tissue types and Th2 subsets. Interestingly in vivo expression of IL-4 is mostly monoallelic yet there is a small highly activated population of biallelic IL-4 expressing Th2 cells. Physiologically each allele of IL-4 was required for a functional Th2 response with total serum IgE titres up to 4 fold lower in IL-4+/- heterozygous compared to the IL-4+/+ sufficient animals and a significant loss in protective immunity against challenge infections with helminths occurred in the IL-4+/- heterozygous animals. The similarity in deficiencies in Th2 immunity in the IL-4+/- heterozygous and IL-4-/- deficient compared to the IL-4+/+ sufficient animals lead to the proposal that the generation of biallelic Th2 cells may be required for specialised cell-to-cell mediated delivery of tailored activation signals and higher quantities of IL-4 required to mediate fully developed Th2 immune responses.</p>

scholarly journals T Cell Receptor–Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex

2000 ◽  
Vol 191 (11) ◽  
pp. 1869-1880 ◽  
Author(s):  
Masakatsu Yamashita ◽  
Makoto Katsumata ◽  
Makio Iwashima ◽  
Motoko Kimura ◽  
Chiori Shimizu ◽  
...  
Keyword(s):  
Cell Receptor ◽  
Cell Development ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
T Helper ◽  
Signaling Complex ◽  
Th2 Cell ◽  
Interleukin 4 Receptor

The activation of downstream signaling pathways of both T cell receptor (TCR) and interleukin 4 receptor (IL-4R) is essential for T helper type 2 (Th2) cell development, which is central to understanding immune responses against helminthic parasites and in allergic and autoimmune diseases. However, little is known about how these two distinct signaling pathways cooperate with each other to induce Th2 cells. Here, we show that successful Th2 cell development depends on the effectiveness of TCR-induced activation of calcineurin. An inhibitor of calcineurin activation, FK506, inhibited the in vitro anti-TCR–induced Th2 cell generation in a dose-dependent manner. Furthermore, the development of Th2 cells was significantly impaired in naive T cells from dominant-negative calcineurin Aα transgenic mice, whereas that of Th1 cells was less affected. Efficient calcineurin activation in naive T cells upregulated Janus kinase (Jak)3 transcription and the amount of protein. The generation of Th2 cells induced in vitro by anti-TCR stimulation was inhibited significantly by the presence of Jak3 antisense oligonucleotides, suggesting that the Jak3 upregulation is an important event for the Th2 cell development. Interestingly, signal transducer and activator of transcription (STAT)5 became physically and functionally associated with the IL-4R in the anti-TCR–activated developing Th2 cells that received efficient calcineurin activation, and also in established cloned Th2 cells. In either cell population, the inhibition of STAT5 activation resulted in a diminished IL-4–induced proliferation. Moreover, our results suggest that IL-4–induced STAT5 activation is required for the expansion process of developing Th2 cells. Thus, Th2 cell development is controlled by TCR-mediated activation of the Ca2+/calcineurin pathway, at least in part, by modifying the functional structure of the IL-4R signaling complex.

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