scholarly journals Interleukin-4 Receptor α Chain and STAT6 Signaling Inhibit Gamma Interferon but Not Th2 Cytokine Expression within Schistosome Granulomas

2002 ◽  
Vol 70 (10) ◽  
pp. 5651-5658 ◽  
Author(s):  
Ahmed Metwali ◽  
Arthur Blum ◽  
David E. Elliott ◽  
Joel V. Weinstock
Keyword(s):  
T Cells ◽  
Flow Analysis ◽  
Cell Development ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Th2 Cytokine ◽  
Th2 Cell ◽  
Nk T Cells ◽  
Ifn Γ ◽  
Interleukin 4 Receptor

ABSTRACT Compared to wild-type (WT) mice, schistosome granulomas in Stat6 knockout (KO) mice lacked eosinophils and had Th1 features. Interleukin-4 (IL-4) acts through Stat6 in assisting Th2 cell development. The importance of Stat6 for Th2-cell development within schistosome granulomas had not been explored. Therefore we studied gamma interferon (IFN-γ), IL-4, and IL-5 production in granulomas from Stat6 KO and WT mice. Dispersed granuloma cells from Stat6 KO and WT mice made similar amounts of IL-4 and IL-5. Only Stat6 KO granuloma cells released IFN-γ. Granuloma T cells contained most of the IL-4, IL-5, and IFN-γ mRNA and secreted these cytokines. In Stat6 KO mice, 16.6% of the granuloma cells were CD4+. Of these, 10.7% stained for IFN-γ and/or IL-4 by intracytoplasmic flow analysis. Few CD4− T cells stained positively. The IL-4-producing T cells did not stain for DX5 or with labeled α-GalCer CD1d tetramer, suggesting an absence of NK T cells. Thus, conventional Th cells in Stat6 KO granulomas produce IFN-γ and Th2 cytokines. Stat6 limits IFN-γ production but is unnecessary for Th2-cell development or localization within the granuloma.

scholarly journals Populations of Human T Lymphocytes That Traverse the Vascular Endothelium Stimulated by Borrelia burgdorferi Are Enriched with Cells That Secrete Gamma Interferon

2004 ◽  
Vol 72 (3) ◽  
pp. 1530-1536 ◽  
Author(s):  
Edna I. Gergel ◽  
Martha B. Furie
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Vascular Endothelium ◽  
Human Peripheral Blood ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Ifn Γ

ABSTRACT Some diseases are characterized by prevalence in the affected tissues of type 1 T lymphocytes, which secrete gamma interferon (IFN-γ) and other proinflammatory cytokines. For example, type 1 T cells predominate in the lesions of patients with Lyme disease, which is caused by the bacterium Borrelia burgdorferi. We used an in vitro model of the blood vessel wall to test the premise that the vascular endothelium actively recruits circulating type 1 T cells to such lesions. When T lymphocytes isolated from human peripheral blood were examined, the populations that traversed monolayers of resting human umbilical vein endothelial cells (HUVEC) or HUVEC stimulated by interleukin-1β or B. burgdorferi were markedly enriched for T cells that produced IFN-γ compared to the initially added population of T cells. No enrichment was seen for cells that produced interleukin-4, a marker for type 2 T lymphocytes. Very late antigen-4 and CD11/CD18 integrins mediated passage of the T cells across both resting and stimulated HUVEC, and the endothelium-derived chemokine CCL2 (monocyte chemoattractant protein 1) was responsible for the enhanced migration of T cells across stimulated HUVEC. These results suggest that the vascular endothelium may contribute to the selective accumulation of type 1 T cells in certain pathological lesions, including those of Lyme disease.

scholarly journals Gamma Interferon Produced by Antigen-Specific CD4+ T Cells Regulates the Mucosal Immune Responses to Citrobacter rodentium Infection

2010 ◽  
Vol 78 (6) ◽  
pp. 2653-2666 ◽  
Author(s):  
Hideyuki Shiomi ◽  
Atsuhiro Masuda ◽  
Shin Nishiumi ◽  
Masayuki Nishida ◽  
Tetsuya Takagawa ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Gamma Interferon ◽  
Immune Defense ◽  
Interleukin 4 ◽  
Mucosal Inflammation ◽  
Citrobacter Rodentium ◽  
Macrophage Phagocytosis ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the surface of intestinal epithelial cells and causes mucosal inflammation. This bacterium is an ideal model for investigating pathogen-host immune interactions in the gut. It is well known that gene transcripts for Th1 cytokines are highly induced in colonic tissue from mice infected with C. rodentium. However, it remains to be seen whether the Th1 or Th2 cytokines produced by antigen-specific CD4+ T cells provide effective regulation of the host immune defense against C. rodentium infection. To investigate the antigen-specific immune responses, C. rodentium expressing ovalbumin (OVA-C. rodentium), a model antigen, was generated and used to define antigen-specific responses under gamma interferon (IFN-γ)-deficient or interleukin-4 (IL-4)-deficient conditions in vivo. The activation of antigen-specific CD4+ T cells and macrophage phagocytosis were evaluated in the presence of IFN-γ or IL-4 in vitro. IFN-γ-deficient mice exhibited a loss of body weight and a higher bacterial concentration in feces during OVA-C. rodentium infection than C57BL/6 (wild type) or IL-4-deficient mice. This occurred through the decreased efficiency of macrophage phagocytosis and the activation of antigen-specific CD4+ T cells. Furthermore, a deficiency in antigen-specific CD4+ T-cell-expressed IFN-γ led to a higher susceptibility to mucosal and gut-derived systemic OVA-C. rodentium infection. These results show that the IFN-γ produced by antigen-specific CD4+ T cells plays an important role in the defense against C. rodentium.

scholarly journals c-Myb, Menin, GATA-3, and MLL form a dynamic transcription complex that plays a pivotal role in human T helper type 2 cell development

Blood ◽  
2010 ◽  
Vol 116 (8) ◽  
pp. 1280-1290 ◽  
Author(s):  
Yuji Nakata ◽  
Anne C. Brignier ◽  
Shenghao Jin ◽  
Yuan Shen ◽  
Stephen I. Rudnick ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Direct Interaction ◽  
Cell Development ◽  
Interleukin 4 ◽  
Effector Memory ◽  
Memory Cells ◽  
Th2 Cell ◽  
Core Elements

Abstract GATA-3 and c-Myb are core elements of a transcriptionally active complex essential for human Th2 cell development and maintenance. We report herein mechanistic details concerning the role of these transcription factors in human peripheral blood Th2 cell development. Silencing c-Myb in normal human naive CD4+ cells under Th2 cell-promoting conditions blocked up-regulation of GATA-3 and interleukin-4, and in effector/memory CD4+ T cells, decreased expression of GATA-3 and Th2 cytokines. In primary T cells, c-Myb allows GATA-3 to autoactivate its own expression, an event that requires the direct interaction of c-Myb and GATA-3 on their respective binding sites in promoter of GATA-3. Immunoprecipitation revealed that the c-Myb/GATA-3 complex contained Menin and mixed lineage leukemia (MLL). MLL recruitment into the c-Myb-GATA-3-Menin complex was associated with the formation Th2 memory cells. That MLL-driven epigenetic changes were mechanistically important for this transition was suggested by the fact that silencing c-Myb significantly decreased the methylation of histone H3K4 and the acetylation of histone H3K9 at the GATA-3 locus in developing Th2 and CD4+ effector/memory cells. Therefore, c-Myb, GATA-3, and Menin form a core transcription complex that regulates GATA-3 expression and, with the recruitment of MLL, Th2 cell maturation in primary human peripheral blood T cells.

scholarly journals Anisakis pegreffii-Induced Airway Hyperresponsiveness Is Mediated by Gamma Interferon in the Absence of Interleukin-4 Receptor Alpha Responsiveness

2010 ◽  
Vol 78 (9) ◽  
pp. 4077-4086 ◽  
Author(s):  
Frank Kirstein ◽  
William G. C. Horsnell ◽  
Natalie Nieuwenhuizen ◽  
Bernhard Ryffel ◽  
Andreas L. Lopata ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Airway Hyperresponsiveness ◽  
Allergic Airway Inflammation ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Wild Type ◽  
Receptor Alpha ◽  
Immunological Mechanisms ◽  
Ifn Γ ◽  
Interleukin 4 Receptor

ABSTRACT Infection with the fish parasite Anisakis following exposure to contaminated fish can lead to allergic reactions in humans. The present study examined the immunological mechanisms underlying the development of allergic airway inflammation in mice after different routes of sensitization to Anisakis. Wild-type and interleukin-4 receptor alpha (IL-4Rα)-deficient BALB/c mice were sensitized intraperitoneally with live or heat-killed Anisakis larvae or by intranasal administration of an Anisakis extract and were subsequently challenged intranasally with an Anisakis extract. Both routes of sensitization induced IL-4Rα-dependent allergic airway responses, whereas allergen-specific antibody responses developed only when mice were sensitized intraperitoneally. Intranasal sensitization induced airway hyperresponsiveness (AHR) in wild-type mice only, showing that AHR was IL-4/IL-13 dependent. Unexpectedly, infection with Anisakis larvae induced AHR in both wild-type and IL-4Rα-deficient mice. IL-4Rα-independent AHR was mediated by gamma interferon (IFN-γ), as evidenced by the fact that in vivo neutralization of IFN-γ abrogated AHR. Together, these results demonstrate that both infection with larvae and inhalational exposure to Anisakis proteins are potent routes of allergic sensitization to Anisakis, explaining food- and work-related allergies in humans. Importantly for diagnosis, allergic airway inflammation can be independent of detectable Anisakis-specific antibodies. Moreover, depending on the route of sensitization, AHR can be induced either by IL-4/IL-13 or by IFN-γ.

scholarly journals Contribution of NK, NK T, γδ T, and αβ T Cells to the Gamma Interferon Response Required for Liver Protection against Trypanosoma cruzi

2006 ◽  
Vol 74 (4) ◽  
pp. 2031-2042 ◽  
Author(s):  
Luiz Roberto Sardinha ◽  
Rosa Maria Elias ◽  
Tainá Mosca ◽  
Karina R. B. Bastos ◽  
Cláudio R. F. Marinho ◽  
...  
Keyword(s):  
T Cells ◽  
Trypanosoma Cruzi ◽  
Nk Cells ◽  
Γδ T Cells ◽  
Gamma Interferon ◽  
Cell Populations ◽  
Liver Protection ◽  
Nk T Cells ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT In the present work, we show that intracellular Trypanosoma cruzi is rarely found in the livers of acutely infected mice, but inflammation is commonly observed. The presence of numerous intrahepatic amastigotes in infected gamma interferon (IFN-γ)-deficient mice corroborates the notion that the liver is protected by an efficient local immunity. The contribution of different cell populations was suggested by data showing that CD4- and CD8-deficient mice were able to restrain liver parasite growth. Therefore, we have characterized the liver-infiltrating lymphocytes and determined the sources of IFN-γ during acute T. cruzi infection. We observed that natural killer (NK) cells increased by day 7, while T and B cells increased by day 14. Among CD3+ cells, CD4+, CD8+, and CD4− CD8− cell populations were greatly expanded. A large fraction of CD3+ cells were positive for PanNK, a β1 integrin expressed by NK and NK T cells. However, these lymphocytes were not classic NK T cells because they did not express NK1.1 and showed no preferential usage of Vβ8. Otherwise, liver NK T (CD3+ NK1.1+) cells were not increased in acutely infected mice. The majority of PanNK+ CD4+ and PanNK+ CD8+ cells expressed T-cell receptor αβ (TCRαβ), whereas PanNK+ CD4− CD8− cells were positive for TCRγδ. In fact, γδ T cells showed the most remarkable increase (40- to 100-fold) among liver lymphocytes. Most importantly, intracellular analysis revealed high levels of IFN-γ production at day 7 by NK cells and at day 14 by CD4+, CD8+, and CD4− CD8− TCRγδ+ cells. We concluded that NK cells are a precocious source of IFN-γ in the livers of acutely infected mice, and, as the disease progresses, conventional CD4+ and CD8+ T cells and γδ T cells, but not classic NK-T cells, may provide the IFN-γ required for liver protection against T. cruzi.

scholarly journals Disruption of the ICOS-B7RP-1 Costimulatory Pathway Leads to Enhanced Hepatic Immunopathology and Increased Gamma Interferon Production by CD4 T Cells in Murine Schistosomiasis

2003 ◽  
Vol 71 (7) ◽  
pp. 4040-4044 ◽  
Author(s):  
Laura I. Rutitzky ◽  
Engin Özkaynak ◽  
James B. Rottman ◽  
Miguel J. Stadecker
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Costimulatory Molecule ◽  
Lymphocyte Activation ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Ifn Γ ◽  
Egg Antigen ◽  
Costimulatory Pathway

ABSTRACT Morbidity and mortality in schistosomiasis are largely due to an immune response mediated by CD4 T lymphocytes. Since lymphocyte activation is shaped by costimulatory signals, the specific functions of different costimulatory pathways are of increasing interest. We now examined the role of the inducible costimulatory molecule (ICOS) and its ligand B7-related protein 1 (B7RP-1) in the experimental murine schistosome infection by blocking this costimulatory pathway with monoclonal antibody against ICOS, administered daily by intraperitoneal injection during the patent phase of the disease. The treated mice exhibited enhanced hepatic immunopathology characterized by enlarged egg granulomas and pronounced parenchymal inflammation with hepatocellular necrosis, resulting in elevated liver enzyme levels in serum. Most strikingly, there was a sharp increase in gamma interferon (IFN-γ) production by schistosome egg antigen-stimulated granuloma cells, bulk mesenteric lymph node (MLN) cells, and purified MLN CD4 T cells, which contrasted with a more discreet change in the Th2-type cytokines interleukin 4 (IL-4) and IL-10. These findings suggest that the ICOS-B7RP-1 costimulatory pathway serves primarily to control IFN-γ production, thereby promoting a cytokine environment conducive to limited hepatic damage.

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.

scholarly journals c-Jun NH2-Terminal Kinase 2 Inhibits Gamma Interferon Production during Anaplasma phagocytophilum Infection

2007 ◽  
Vol 76 (1) ◽  
pp. 308-316 ◽  
Author(s):  
Joao H. F. Pedra ◽  
Jochen Mattner ◽  
Jian Tao ◽  
Steven M. Kerfoot ◽  
Roger J. Davis ◽  
...  
Keyword(s):  
T Cells ◽  
Strong Evidence ◽  
Anaplasma Phagocytophilum ◽  
Critical Role ◽  
Regulatory Protein ◽  
Inhibitory Effect ◽  
Gamma Interferon ◽  
Interferon Production ◽  
Nk T Cells ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) plays a critical role in the early eradication of Anaplasma phagocytophilum. However, the mechanisms that regulate IFN-γ production upon infection remain poorly understood. Here we show that c-Jun NH2-terminal kinase 2 (JNK2) inhibits IFN-γ production during A. phagocytophilum infection. jnk2-null mice were more refractory to infection with A. phagocytophilum and produced increased levels of IFN-γ after challenge with the pathogen. The resistance of jnk2-null mice to A. phagocytophilum infection was due to elevated levels of IFN-γ secreted by conventional and natural killer (NK) T cells. The administration of α-galactosylceramide, a strong NK T-cell agonist, increased IFN-γ release and protected mice from A. phagocytophilum, further demonstrating the inhibitory effect of JNK2 on IFN-γ production. Collectively, these findings provide strong evidence that JNK2 is an important regulatory protein for IFN-γ secretion upon challenge with A. phagocytophilum.

scholarly journals Control of Leishmania infantum Infection Is Associated with CD8+ and Gamma Interferon- and Interleukin-5-Producing CD4+ Antigen-Specific T Cells

1999 ◽  
Vol 67 (11) ◽  
pp. 5559-5566 ◽  
Author(s):  
Charles Mary ◽  
Valérie Auriault ◽  
Bernard Faugère ◽  
Alain J. Dessein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Visceral Leishmaniasis ◽  
Large Fraction ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
T Cell Clones ◽  
Asymptomatic Patients ◽  
Cell Clones ◽  
Ifn Γ

ABSTRACT Visceral leishmaniasis is a severe and lethal disease caused by the protozoan parasites of the genus Leishmania. In areas where leishmaniasis is endemic, most infected individuals control the infection and remain asymptomatic; chemotherapy of visceral leishmaniasis restores some immunity which protects against relapses. In the present study, Leishmania-specific T-cell clones were established from six asymptomatic and five cured patients. Cytokines production by these clones was analyzed. A large fraction of the parasite-specific T-cell clones from asymptomatic patients were CD8+ and produced high amounts of gamma interferon (IFN-γ). Most CD4+ T-cell clones from two asymptomatic subjects exhibited an unusual phenotype: production of high levels of IFN-γ low levels of interleukin-4, (IL-4), but high levels of IL-5. In contrast, only few parasite-specific CD8+ T-cell clones were obtained from cured patients after chemotherapy; moreover, CD4+ T-cell clones from these patients exhibited an heterogeneous profile of cytokines from Th1-like to Th2-like phenotypes. These results point to CD8+ T cells and to IL-5- and IFN-γ-producing CD4+ T cells as possible contributors to human resistance to Leishmania infection. They should stimulate new immunological approaches in the control of this disease.

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