scholarly journals Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
M. Sambucci ◽  
F. Laudisi ◽  
F. Novelli ◽  
E. Bennici ◽  
M. M. Rosado ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Inflammatory Responses ◽  
Inhibitory Effect ◽  
Th2 Cells ◽  
Cell Functions ◽  
Th2 Cell ◽  
Gene Ablation ◽  
Immune Mediated ◽  
Parp 1 ◽  
Th1 And Th2

T cell differentiation to effector Th cells such as Th1 and Th2 requires the integration of multiple synergic and antagonist signals. Poly(ADP-ribosy)lation is a posttranslational modification of proteins catalyzed by Poly(ADP-ribose) polymerases (PARPs). Recently, many reports showed that PARP-1, the prototypical member of the PARP family, plays a role in immune/inflammatory responses. Consistently, its enzymatic inhibition confers protection in several models of immune-mediated diseases, mainly through an inhibitory effect on NF-κB (and NFAT) activation. PARP-1 regulates cell functions in many types of immune cells, including dendritic cells, macrophages, and T and B lymphocytes. Our results show that PARP-1KO cells displayed a reduced ability to differentiate in Th2 cells. Under both nonskewing and Th2-polarizing conditions, naïve CD4 cells from PARP-1KO mice generated a reduced frequency of IL-4+cells, produced less IL-5, and expressed GATA-3 at lower levels compared with cells from wild type mice. Conversely, PARP-1 deficiency did not substantially affect differentiation to Th1 cells. Indeed, the frequency of IFN-γ+cells as well as IFN-γproduction, in nonskewing and Th1-polarizing conditions, was not affected by PARP-1 gene ablation. These findings demonstrate that PARP-1 plays a relevant role in Th2 cell differentiation and it might be a target to be exploited for the modulation of Th2-dependent immune-mediated diseases.

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 The Cxxc1 subunit of the Trithorax complex directs epigenetic licensing of CD4+ T cell differentiation

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
Masahiro Kiuchi ◽  
Atsushi Onodera ◽  
Kota Kokubo ◽  
Tomomi Ichikawa ◽  
Yuki Morimoto ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Allergic Airway Inflammation ◽  
T Cell Differentiation ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
Th2 Differentiation ◽  
Later Phase ◽  
Th1 And Th2

Different dynamics of gene expression are observed during cell differentiation. In T cells, genes that are turned on early or turned off and stay off have been thoroughly studied. However, genes that are initially turned off but then turned on again after stimulation has ceased have not been defined; they are obviously important, especially in the context of acute versus chronic inflammation. Using the Th1/Th2 differentiation paradigm, we found that the Cxxc1 subunit of the Trithorax complex directs transcription of genes initially down-regulated by TCR stimulation but up-regulated again in a later phase. The late up-regulation of these genes was impaired either by prolonged TCR stimulation or Cxxc1 deficiency, which led to decreased expression of Trib3 and Klf2 in Th1 and Th2 cells, respectively. Loss of Cxxc1 resulted in enhanced pathogenicity in allergic airway inflammation in vivo. Thus, Cxxc1 plays essential roles in the establishment of a proper CD4+ T cell immune system via epigenetic control of a specific set of genes.

Interleukin-4 Blood Concentrations in Early and Metastatic Human Solid Neoplasms

1997 ◽  
Vol 12 (2) ◽  
pp. 75-78 ◽  
Author(s):  
P. Lissoni ◽  
D. Merlini ◽  
D. Pirato ◽  
S. Meregalli
Keyword(s):  
Cancer Patients ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Control Group ◽  
Blood Levels ◽  
Neoplastic Disease ◽  
Blood Concentrations ◽  
Mean Values ◽  
Cell Functions ◽  
Th2 Cell

Blood levels of the immunosuppressive cytokines IL-6 and IL-10 are often abnormally high in patients with advanced cancer. However, since IL-6 and IL-10 may be produced by macrophages and TH2 cells, the evidence of abnormally high values of IL-6 and/or IL-10 may reflect hyperactivation either of the macrophage system or of TH2 cell functions. In contrast, IL-4 is almost completely produced by the TH2 lymphocytes. Therefore, evaluation of IL-4 levels could help to differentiate macrophage from TH2 cell hyperactivation. This study was performed to investigate IL-4 serum levels in a group of cancer patients in relation to the stage of disease and to the secretion of other cytokines. The study included 50 patients, 28 of whom showed distant organ metastases. Lung cancer and gastrointestinal cancers were the most frequent neoplasms in our patients. The control group consisted of 60 healthy subjects. IL-4 was measured by the Elisa method. No patient showed high levels of IL-4. No significant differences were seen between controls and cancer patients, nor between metastatic and non-metastatic patients. In addition, no significant differences in IL-4 mean values were found between patients with normal or high levels of IL-6 and IL-10, or between patients with normal or low IL-2 concentrations. This preliminary study seems to exclude cancer-related abnormally high secretion of IL-4. Therefore, the high levels of IL-6 and/or IL-10 often occurring in advanced neoplastic disease would mainly depend on macrophage production.

scholarly journals Downregulation of miRNA-451a Promotes the Differentiation of CD4+ T Cells towards Th2 Cells by Upregulating ETS1 in Childhood Asthma

2020 ◽  
pp. 1-11
Author(s):  
Tianyue  Wang ◽  
Qianlan Zhou ◽  
Yunxiao Shang
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Peripheral Blood Lymphocytes ◽  
Cell Polarization ◽  
Luciferase Assay ◽  
Th2 Cells ◽  
Th2 Cell ◽  
Novel Target

Children exposed to common aeroallergens may develop asthma that progresses into adulthood. Inflammation regulated by T helper 2 (Th2) cells, a specific subpopulation of CD4+ T lymphocytes, is involved in asthmatic injury. Herein, our microarray data indicated that microRNA-451a-5p (miRNA-451a) expression decreased by 4.6-fold and ETS proto-oncogene 1 (ETS1) increased by 2.2-fold in the peripheral blood lymphocytes isolated from asthmatic children (<i>n</i> = 4) as compared to control individuals (<i>n</i> = 4). The negative correlation between miRNA-451a and ETS1 was further validated in 40 CD4+ T cell samples (10 healthy vs. 30 asthmatic samples). In vitro, naïve CD4+ T cells isolated from control individuals were cultured under Th2 cell polarizing condition. miRNA-451a expression decreased while ETS1 increased in CD4+ T cells in the setting of Th2 cell polarization. Moreover, miRNA-451a knockdown enhanced Th2 cell polarization – cells positive for both GATA3 (GATA binding protein 3, a Th2-transcription factor) and CD4 increased, and the generation of Th2 cell cytokines, interleukin (IL)5 and IL13, increased. In contrast, miRNA-451a overexpression inhibited Th2 cell differentiation. Interestingly, dual-Luciferase assay proved ETS1 as a novel target of miRNA-451a. Moreover, enforced expression of ETS1 partially restored miRNA-451a-induced inhibition of IL5 and IL13, and increased the GATA3+CD4+ cell population. Collectively, our work demonstrates that downregulation of miRNA-451a upregulates ETS1 expression in CD4+ T cells, which may contribute to Th2 cell differentiation in pediatric asthma.

scholarly journals A Regulatory Role for Interleukin 4 in Differential Inflammatory Responses in the Lung following Infection of Mice Primed with Th1- or Th2-Inducing Pertussis Vaccines

2000 ◽  
Vol 68 (3) ◽  
pp. 1383-1390 ◽  
Author(s):  
Peter McGuirk ◽  
Kingston H. G. Mills
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Th2 Cells ◽  
Infection Model ◽  
Local Production ◽  
Local Inflammatory Response ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Th1 And Th2

ABSTRACT Protection against infectious pathogens at mucosal surfaces is dependent on local antibody responses, production of inflammatory mediators, and recruitment of immune effector cells to the site of infection. Since Th1 and Th2 cells produce cytokines with pro- and anti-inflammatory activities, immunization with vaccines that induce these T-cell subtypes may regulate the subsequent inflammatory response to infection. We have demonstrated that immunization of mice with pertussis whole-cell or acellular vaccines (Pw or Pa) selectively induces Th1 and Th2 cells, respectively. In this study we have used a murine respiratory-infection model to demonstrate that priming with a Th1- or Th2-inducing pertussis vaccine can influence the local inflammatory response and immune effector cells in the lung following aerosol challenge with Bordetella pertussis. Analysis of bronchoalveolar lavage (BAL) fluid taken during the course of B. pertussis infection of naı̈ve mice or mice immunized with Pw revealed an early influx of neutrophils and local production of interleukin 1β (IL-1β) in the lungs. In contrast, neutrophil infiltration and IL-1β production were not observed following challenge of mice immunized with the Th2-inducing Pa. Conversely, during infection local production of IL-6 and IL-1ra was significantly greater in mice immunized with Pa than in those immunized with Pw. Studies of knockout mice revealed neutrophil and lymphocyte infiltration in the lungs following B. pertussis infection of IL-4-defective (IL-4−/−) mice but not in wild-type mice immunized with Pa. Furthermore, the levels of IL-1β, IL-6, and IL-1ra in Pa-immunized IL-4−/− mice were comparable to those in mice immunized with Pw. These results demonstrate distinct influences of Th1- and Th2-inducing vaccines on the protective inflammatory responses in the lungs following challenge with B. pertussis and implicate IL-4 as an important regulator of inflammatory-cell recruitment.

scholarly journals Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

2009 ◽  
Vol 206 (11) ◽  
pp. 2407-2416 ◽  
Author(s):  
Jyoti Das ◽  
Guangwen Ren ◽  
Liying Zhang ◽  
Arthur I. Roberts ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Th2 Cells ◽  
Th17 Cell Differentiation ◽  
Th1 And Th2

Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor γt, a Th17-specific transcription factor. Interestingly, in Stat-6−/−T-bet−/− mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6−/−T-bet−/− mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.

scholarly journals Responsiveness of Naive CD4 T Cells to Polarizing Cytokine Determines the Ratio of Th1 and Th2 Cell Differentiation

2006 ◽  
Vol 176 (3) ◽  
pp. 1553-1560 ◽  
Author(s):  
Natallia Mikhalkevich ◽  
Brian Becknell ◽  
Michael A. Caligiuri ◽  
Michael D. Bates ◽  
Richard Harvey ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Th2 Cell ◽  
Th1 And Th2

scholarly journals Distinct Role of Antigen-Specific T Helper Type 1 (Th1) and Th2 Cells in Tumor Eradication in Vivo

1999 ◽  
Vol 190 (5) ◽  
pp. 617-628 ◽  
Author(s):  
Takashi Nishimura ◽  
Kenji Iwakabe ◽  
Masashi Sekimoto ◽  
Yasushi Ohmi ◽  
Takashi Yahata ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Th2 Cells ◽  
T Helper ◽  
Th1 Cell ◽  
Th2 Cell ◽  
Tumor Eradication ◽  
Th1 And Th2

The role of T helper type 1 (Th1) and Th2 cells in tumor immunity was investigated using Th cells induced from ovalbumin (OVA)-specific T cell receptor transgenic mice. Although Th1 cells exhibited stronger cytotoxicity than Th2 cells, both cell types completely eradicated tumors when transferred into mice bearing A20 tumor cells transfected with the OVA gene (A20-OVA). Th1 cells eradicated the tumor mass by inducing cellular immunity, whereas Th2 cells destroyed the tumor by inducing tumor necrosis. Both Th1 and Th2 cells required CD8+ T cells to eliminate tumors, and neither of these cells were able to completely eliminate A20-OVA tumors from T and B cell–deficient RAG2−/− mice. Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8+ cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy. Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1–dependent cell–cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy. These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.

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