scholarly journals Mast Cells Stimulated with Peptidoglycan from Staphylococcus aureus Augment the Development of Th1 Cells

2018 ◽  
Vol 21 ◽  
pp. 296-304
Author(s):  
Katsuhiko Matsui ◽  
Saeko Kanai ◽  
Manami Ikuta ◽  
Saki Horikawa
Keyword(s):  
Staphylococcus Aureus ◽  
Mast Cells ◽  
Chronic Inflammation ◽  
Cell Development ◽  
Th1 Cells ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th2 Cell ◽  
Helper Type

Background: The skin of patients with atopic dermatitis (AD) is superficially colonized by Staphylococcus aureus. We have previously found that percutaneous permeation of peptidoglycan (PEG) from S. aureus increases the number of mast cells in the dermis, as seen in skin lesions of AD patients. The purpose of the present study was to clarify the influence of PEG on T helper type 1 (Th1)/ T helper type 2 (Th2) cell development mediated by mast cells. Methods: Mast cells were induced by long-term culture of murine spleen cells in medium supplemented with tumor necrosis factor (TNF)- a. Ovalbumin (OVA) peptide-pulsed mast cells were incubated with naïve Th cells in the presence or absence of PEG. Five days later, Th cells in the culture were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and Th1/Th2 cytokine production was investigated by enzyme-linked immunosorbent assay. Results: It was confirmed that the mast cells we obtained had surface expression of I-Ad, worked as antigen-presenting cells, and induced Th1 cell and Th2 cell development. The stimulation of mast cells with PEG enhanced the development of Th1 cells but not that of Th2 cells. The increase of Th1 cell development stimulated by PEG was associated with an increase in the expression of Notch ligand Delta 1 in the mast cells. Furthermore, treatment of mast cells with the macrolide antibiotic josamycin suppressed Th1 cell development and this was correlated with a reduction of both Delta 1 expression and interleukin (IL)-12 production in mast cells. Conclusions: Colonization of S. aureus on the lesioned skin of AD patients contributes to not only an increase in the number of mast cells but also Th1 cell development mediated by mast cells in the dermis and subsequent induction of chronic inflammation, which is characterized by up-regulation of the Th1 cytokine, interferon (IFN)- g. Therefore, application of josamycin to the lesional skin of AD patients may provide relief from chronic inflammation mediated by mast cells.

scholarly journals Norfloxacin, a Fluoroquinolone Antibiotic, Inhibits Langerhans Cell-Mediated Th1 and Th2 Cell Development

2019 ◽  
Vol 22 ◽  
pp. 122-130 ◽  
Author(s):  
Katsuhiko Matsui ◽  
Azusa Kashima ◽  
Ayaka Motegi
Keyword(s):  
Topical Application ◽  
Skin Lesions ◽  
Cell Development ◽  
T Helper ◽  
Down Regulation ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Fluoroquinolone Antibiotic ◽  
Th1 And Th2 ◽  
Helper Type

Background: It is widely acknowledged that Langerhans cells (LCs) play a primary role in the polarization of T helper type 1 (Th1) or T helper type 2 (Th2) immune responses. Our aim was to find fluoroquinolone (“new quinolone”) antibiotics that would inhibit LC-mediated Th2 cell development. Methods: Expression of LC surface molecules was investigated using the reverse transcriptase polymerase chain reaction. The effects of fluoroquinolone antibiotics on T-cell immunoglobulin and mucin domain-containing protein (TIM)-4 expression in LCs were examined to predict whether they would inhibit Th2 cell development. Mice were primed via the hind footpad with ovalbumin (OVA) peptide-pulsed LCs that had been treated with a selected fluoroquinolone antibiotic, then 5 days later the cytokine response in popliteal lymph nodes was examined by enzyme-linked immunosorbent assay. Results: Norfloxacin was selected as a candidate inhibitor of Th2 cell development. As expected, OVA peptide-pulsed LCs that had been treated with norfloxacin and injected into the hind footpads of mice inhibited Th2 cell development, as represented by down-regulation of interleukin (IL)-4 production, as well as Th1 cell development, as represented by down-regulation of interferon (IFN)- g production. This additional inhibition of Th1 cell development was accompanied by suppression of CD40 expression in LCs. In addition, Staphylococcus aureus strains isolated from skin lesions of patients with atopic dermatitis (AD) were more susceptible to norfloxacin than to gentamicin. Topical treatment with norfloxacin significantly suppressed the increase in the skin severity score in NC/Nga mice with AD-like skin lesions. This suppressive effect was associated with a decrease in the production of IFN-g and IL-4 in auricular lymph node cells. Conclusions: The present results show that topical application of norfloxacin inhibits the development of AD-like skin lesions in NC/Nga mice. This suggests that topical application of norfloxacin to AD lesions colonized with S. aureus would act on both superficial S. aureus and epidermal LCs, thus possibly inhibiting the development of Th1 and Th2 cells in vivo, and controlling the severity of AD.

scholarly journals Effects of anti-allergy drugs on Th1 cell and Th2 cell development mediated by Langerhans cells

2020 ◽  
Vol 23 ◽  
pp. 412-421
Author(s):  
Katsuhiko Matsui ◽  
Xiaolei Shi ◽  
Sayuko Komori ◽  
Atsumi Higuchi
Keyword(s):  
Topical Application ◽  
Langerhans Cells ◽  
Skin Lesions ◽  
Cell Development ◽  
Enzyme Linked Immunosorbent Assay ◽  
T Helper ◽  
Down Regulation ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Helper Type

Background: It is well known that Langerhans cells (LCs) work as the primary orchestrators in polarization towards T helper type 1 (Th1) or T helper type 2 (Th2) immune responses. In this study, we examined the effects of various anti-allergy drugs against the Th2 cell development by LCs. Methods: The expression of cell surface molecules on LCs was investigated using reverse transcriptase polymerase chain reaction. The effects of anti-allergy drugs on T-cell immunoglobulin and mucin domain-containing protein (TIM)-4 expression in LCs were examined to predict whether they would inhibit Th2 cell development. Next, mice were primed via the hind footpad with ovalbumin (OVA)-pulsed LCs that had been treated with selected anti-allergy drugs. After 5 days, the cytokine response in the popliteal lymph nodes was investigated by enzyme-linked immunosorbent assay. The therapeutic effects of a selected drug on atopic dermatitis (AD) were assessed using AD-like skin lesions of NC/Nga mice. Results: The first-generation histamine H1 receptorantagonists, cyproheptadine and promethazine, and the second-generation histamine H1 receptor antagonists, emedastine and loratadine, were selected as candidate inhibitors of Th2 cell development. As expected, OVA peptide-pulsed LCs that had been treated with each drug and injected into the hind footpads of mice inhibited Th2 cell development, as represented by down-regulation of interleukin (IL)-4 production. Furthermore, the LCs that had been treated withemedastine also inhibited Th1 cell development, as represented by down-regulation of interferon (IFN)-g production. This additional inhibition of Th1 cell development was accompanied by suppression of CD40 expression in LCs. Therefore, the therapeutic effect of emedastine on AD was examined. Topical application of emedastine significantly suppressed the increase in the skin severity score in NC/Nga mice with AD-like skin lesions. This suppressive effect was associated with a decrease in the production of IFN-g and IL-4 in auricular lymph node cells. Conclusions: These results suggest that topical application of emedastine to skin lesions of patients with AD may provide clinical benefits through the inhibition of both Th1 cell and Th2 cell development mediated by LCs.

scholarly journals No audible wheezing

2005 ◽  
Vol 201 (12) ◽  
pp. 1869-1873 ◽  
Author(s):  
Joshua A. Boyce ◽  
K. Frank Austen
Keyword(s):  
Mast Cells ◽  
Mouse Models ◽  
Airway Hyperresponsiveness ◽  
Pulmonary Inflammation ◽  
Genetic Differences ◽  
Mouse Strains ◽  
T Helper ◽  
Th2 Cell ◽  
Helper Type

Mouse models of T helper type 2 (Th2) cell–biased pulmonary inflammation have elucidated mechanisms of sensitization, cell traffic, and induced airway hyperresponsiveness (AHR). Nonetheless, most mice lack intrinsic AHR, a central property of human asthma, and disparities persist regarding the contributions of eosinophils and mast cells and the sensitivity to induced AHR in the commonly used mouse strains. We suggest that these discordances, reflecting methodological and genetic differences, may be informative for understanding heterogeneity of human asthma.

GATA-3 Requires C-Myb to Auto-Regulate Its Own Expression in Normal Human Peripheral Blood Lymphocytes Undergoing T Helper Type 2 (Th2) Cell Development

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2575-2575
Author(s):  
Yuji Nakata ◽  
Shenghao Jin ◽  
Yuan Shen ◽  
Alan M. Gewirtz
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Human Peripheral Blood ◽  
Cell Formation ◽  
Cell Development ◽  
Peripheral Blood Lymphocytes ◽  
T Helper ◽  
Th1 Cell ◽  
Th2 Cell

Abstract The c-myb protooncogene encodes a transcription factor, c-Myb, which is highly expressed in immature hematopoietic cells. c-Myb is required for many critical aspects of blood cell development including lineage fate selection, proliferation, and at multiple time points during early myeloid, and B and T lymphoid cell development. GATA-3, which belongs to a family of zinc finger transcription factors, is also required at several steps in early T cell development, and specifically in regard to this communication, for the development of T helper type 2 (Th2) cells. A recent study by Maurice et al (EMBO2007, 26:3629–3640) reported that c-myb regulates T helper cell lineage commitment in developing mouse thymocytes via regulation of GATA-3 expression. As we were unaware of any studies that have addressed the role of c-Myb and GATA-3 in normal human peripheral blood lymphocytes (PBL), we explored the potential regulatory relationship between these transcription factors in cells of this type. Proceeding from the murine studies, we performed a chromatin immunoprecipitation assay (ChIP) which showed that c-Myb bound the GATA-3 downstream promoter in naïve CD4+ T cells under conditions designed to promote Th2 growth. Such binding was not observed in cells stimulated under Th1 promoting conditions. The interaction of c-Myb and GATA-3 proteins was also detected in cell lysates under Th2 cell promoting conditions by immunoprecipitation with both anti-c-Myb, and anti-GATA-3 polyclonal antibodies. Of note, immunoprecipitation with these same antibodies did not show binding of either protein to STAT6. Additional studies revealed that c-Myb activated a GATA-3 minimal promoter by direct binding to a conserved c-Myb binding site in peripheral blood T cells. Of even greater interest, in 293T cells, GATA-3 activated its own promoter ~6 fold when c-Myb was co-expressed in 293T cells. In the absence of c-Myb, GATA-3 did not significantly activate its own promoter in these cells. We have recently shown that c-Myb binds to MLL via menin. A ChIP assay also showed that MLL and Menin bound to the GATA-3 promoter suggesting that c-Myb and GATA-3 form a co-activator complex on the GATA-3 promoter with MLL. Finally, to explore the role of c-myb expression in human peripheral blood naive CD4+ T cells, we employed c-Myb targeted, and control, short hairpin RNA (shRNA) expressed from a lentivirus vector. This strategy yielded a sequence specific 80–90% knockdown of c-Myb expression in our hands. Stimulation of naive peripheral blood CD4+ T cells expressing the c-Myb directed shRNA with cytokines promoting Th2 cell formation (IL-4, IL-2, and anti-IL-12 antibody) blocked the up-regulation of GATA-3 mRNA expression ~90% compared to cells in which a control shRNA had been expressed. Flow cytometric analysis revealed that intracellular IL-4 expression also was diminished. In contrast, silencing c-myb had no effect on T-bet mRNA expression, or intracellular interferon-expression in the cells induced to undergo Th1 cell formation with IL-12, IL-2 and anti-IL-4 antibody. We conclude from these studies that c-Myb regulates developmental programs specific for Th2, as opposed to Th1, cell development. We hypothesize that such control is exerted in peripheral blood T lymphocytes, at least in part, through direct control of GATA-3, whose expression is auto-regulated with the assistance of c-Myb, and perhaps MLL, acting as transcriptional co-factors.

scholarly journals Deficiency in the Transcription Factor Interferon Regulatory Factor (Irf)-2 Leads to Severely Compromised Development of Natural Killer and T Helper Type 1 Cells

2000 ◽  
Vol 192 (3) ◽  
pp. 325-336 ◽  
Author(s):  
Michael Lohoff ◽  
Gordon S. Duncan ◽  
David Ferrick ◽  
Hans-Willi Mittrücker ◽  
Susi Bischof ◽  
...  
Keyword(s):  
Natural Killer ◽  
Leishmania Major ◽  
Nk Cell ◽  
Regulatory Element ◽  
Cell Development ◽  
T Helper ◽  
Regulatory Factor ◽  
Th1 Cell ◽  
Helper Type

Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1–mediated transcriptional regulation of IFN-inducible genes. IRF-1−/− mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1−/− mice, IRF-2−/− mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1−/− and IRF-2−/− mice, but the underlying mechanism differs. NK (but not NK+ T) cell numbers are decreased in IRF-2−/− mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for normal generation of Th1 responses and for NK cell development in vivo. In this particular circumstance the absence of IRF-2 cannot be compensated for by the presence of IRF-1 alone. Mechanistically, IRF-2 may act as a functional agonist rather than antagonist of IRF-1 for some, but not all, IFN-stimulated regulatory element (ISRE)-responsive genes.

scholarly journals Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization

2005 ◽  
Vol 201 (4) ◽  
pp. 627-636 ◽  
Author(s):  
Claudia Traidl-Hoffmann ◽  
Valentina Mariani ◽  
Hubertus Hochrein ◽  
Kathrin Karg ◽  
Hermann Wagner ◽  
...  
Keyword(s):  
Pollen Grains ◽  
Cell Polarization ◽  
Interleukin 12 ◽  
Upper Respiratory Tract ◽  
T Helper ◽  
Bioactive Lipids ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Helper Type

Pollen grains induce allergies in susceptible individuals by release of allergens upon contact with mucosal membranes of the upper respiratory tract. We recently demonstrated that pollen not only function as allergen carriers but also as rich sources of bioactive lipids that attract cells involved in allergic inflammation such as neutrophils and eosinophils. Here we demonstrate that soluble factors from birch (Betula alba L.) pollen activate human dendritic cells (DCs) as documented by phenotypical and functional maturation and altered cytokine production. Betula alba L. aqueous pollen extracts (Bet.-APE) selectively inhibited interleukin (IL)-12 p70 production of lipopolysaccharide (LPS)- or CD40L-activated DC, whereas IL-6, IL-10, and TNFα remained unchanged. Presence of Bet.-APE during DC activation resulted in DC with increased T helper type 2 (Th2) cell and reduced Th1 cell polarizing capacity. Chemical analysis of Bet.-APE revealed the presence of phytoprostanes (dinor isoprostanes) with prostaglandin E1-, F1-, A1-, or B1-ring systems of which only E1-phytoprostanes dose dependently inhibited the LPS-induced IL-12 p70 release and augmented the Th2 cell polarizing capacity of DC. These results suggest that pollen-derived E1-phytoprostanes not only resemble endogenous prostaglandin E2 structurally but also functionally in that they act as regulators that modulate human DC function in a fashion that favors Th2 cell polarization.

Expression of Tyk2 in dendritic cells is required for IL-12, IL-23, and IFN-γ production and the induction of Th1 cell differentiation

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 553-560 ◽  
Author(s):  
Naoki Tokumasa ◽  
Akira Suto ◽  
Shin-ichiro Kagami ◽  
Shunsuke Furuta ◽  
Koichi Hirose ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cell Differentiation ◽  
Cpg Odn ◽  
T Helper ◽  
Dc Functions ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Ifn Γ ◽  
Antigen Presenting

Abstract It is well documented that dendritic cells (DCs), representative antigen-presenting cells, are important sources of Th1-promoting cytokines and are actively involved in the regulation of T-helper–cell differentiation. However, the intracellular event that regulates this process is still largely unknown. In this study, we examined the role of Tyk2, a JAK kinase that is involved in the signaling pathway under IL-12 and IL-23, in DC functions. While the differentiation and maturation of DCs was normal in Tyk2-deficient (Tyk2−/−) mice, IL-12–induced Stat4 phosphorylation was diminished in Tyk2−/− DCs. IL-12–induced IFN-γ production was also significantly diminished in Tyk2−/− DCs to levels similar to those in Stat4−/− DCs. Interestingly, Tyk2−/− DCs were defective in IL-12 and IL-23 production upon stimulation with CpG ODN. Furthermore, Tyk2−/− DCs were impaired in their ability to induce Th1-cell differentiation but not Th2-cell differentiation. Taken together, these results indicate that the expression of Tyk2 in DCs is crucial for the production of Th1-promoting cytokines such as IL-12 and IFN-γ from DCs and thereby for the induction of antigen-specific Th1-cell differentiation.

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 A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

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.

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