Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production
17 Nov 1997-Journal of Experimental Medicine (The Rockefeller University Press)-Vol. 186, Iss: 10, pp 1737-1747
TL;DR: It is suggested that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.
Abstract: Airway inflammation is believed to stimulate mucus production in asthmatic patients. Increased mucus secretion is an important clinical symptom and contributes to airway obstruction in asthma. Activated CD4 Th1 and Th2 cells have both been identified in airway biopsies of asthmatics but their role in mucus production is not clear. Using CD4 T cells from mice transgenic for the OVA-specific TCR, we studied the role of Th1 and Th2 cells in airway inflammation and mucus production. Airway inflammation induced by Th2 cells was comprised of eosinophils and lymphocytes; features found in asthmatic patients. Additionally, there was a marked increase in mucus production in mice that received Th2 cells and inhaled OVA, but not in mice that received Th1 cells. However, OVA-specific Th2 cells from IL-4–deficient mice were not recruited to the lung and did not induce mucus production. When this defect in homing was overcome by administration of TNF-α, IL-4 −/− Th2 cells induced mucus as effectively as IL-4 +/+ Th2 cells. These studies establish a role for Th2 cells in mucus production and dissect the effector functions of IL-4 in these processes. These data suggest that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.
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Patent•
01 Mar 1996TL;DR: In this article, methods for the identification and therapeutic use of compounds as treatments of immune disorders, especially T helper lymphocyte-related disorders, are presented. And methods are provided for the diagnostic evaluation and prognosis of TH cell subpopulation related disorders, for identification of subjects exhibiting a predisposition to such conditions, for monitoring patients undergoing clinical evaluation for the treatment of such disorders, and for monitoring the efficacy of compounds used in clinical trials.
Abstract: The present invention relates to methods and compositions for the treatment and diagnosis of immune disorders, especially T helper lymphocyte-related disorders. For example, genes which are differentially expressed within and among T helper (TH) cells and TH cell subpopulations, which include, but are not limited to TH0, TH1 and TH2 cell subpopulations are identified. Genes are also identified via the ability of their gene products to interact with gene products involved in the differentiation, maintenance and effector function of such TH cells and TH cell subpopulations. The genes identified can be used diagnostically or as targets for therapeutic intervention. In this regard, the present invention provides methods for the identification and therapeutic use of compounds as treatments of immune disorders, especially TH cell subpopulation-related disorders. Additionally, methods are provided for the diagnostic evaluation and prognosis of TH cell subpopulation-related disorders, for the identification of subjects exhibiting a predisposition to such conditions, for monitoring patients undergoing clinical evaluation for the treatment of such disorders, and for monitoring the efficacy of compounds used in clinical trials.
150 citations
TL;DR: It is established that mast cells and mast cell-derived TNF can significantly enhance, by FcRgamma-independent mechanisms, the Ag- and Th17 cell-dependent development of a neutrophil-rich inflammatory response at a site of Ag challenge.
148 citations
Journal Article•
TL;DR: It is concluded that in response to RSV, IL-5 is essential for the influx of eosinophils into the lung and that eosInophils in turn are critical for the development of AHR.
Abstract: Viral respiratory infections can cause bronchial hyperresponsiveness and exacerbate asthma. In mice, respiratory syncytial virus (RSV) infection, which induces an immune response dominated by IFN-gamma, results in airway hyperresponsiveness (AHR) and eosinophil influx into the airways, both of which are prevented by pretreatment with anti-IL-5 Ab. To delineate the role of IL-5, IL-4, and IFN-gamma in the development of RSV-induced AHR and lung eosinophilia, we tested the ability of mice deficient in each of these cytokines to develop these symptoms of RSV infection. Mice deficient in either IL-5, IL-4, or IFN-gamma were administered infectious RSV intranasally, and 6 days later, airway responsiveness to inhaled methacholine was assessed by barometric body plethysmography, and numbers of lung eosinophils and production of IFN-gamma, IL-4, and IL-5 by mononuclear cells from peribronchial lymph nodes were monitored. RSV infection resulted in airway eosinophilia and AHR in both IL-4- and IFN-gamma-deficient mice, but not in IL-5-deficient mice. Reconstitution of IL-5-deficient mice with IL-5 restored these responses and enhanced the responses in IL-4-deficient mice. Anti-VLA-4 (very late Ag-4) treatment prevented lung eosinophilia and AHR following RSV infection and IL-5 reconstitution. We conclude that in response to RSV, IL-5 is essential for the influx of eosinophils into the lung and that eosinophils in turn are critical for the development of AHR. IFN-gamma and IL-4 are not essential for these responses to RSV infection.
143 citations
Cites background from "Induction of Airway Mucus Productio..."
...Furthermore, IL-4 is known to be involved in up-regulation of VCAM-1 on vascular endothelial cells (9), facilitating eosinophil and lymphocyte extravasation; IL-4 is also involved in Th2 cell recruitment to sites of allergic inflammation (47)....
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TL;DR: It is shown that T cell-derived IL-13 plays a key role in regulating AHR, mucus hypersecretion, eotaxin production, and eosinophilia in the allergic lung and is critically linked to downstream effector pathways regulated by eotAXin and STAT6.
Abstract: The potent spasmogenic properties of IL-13 have identified this molecule as a potential regulator of airways hyperreactivity (AHR) in asthma. Although IL-13 is thought to primarily signal through the IL-13Rα1-IL-4Rα complex, the cellular and molecular components employed by this cytokine to induce AHR in the allergic lung have not been identified. By transferring OVA-specific CD4+ T cells that were wild type (IL-13+/+ T cells) or deficient in IL-13 (IL-13−/− T cells) to nonsensitized mice that were then challenged with OVA aerosol, we show that T cell-derived IL-13 plays a key role in regulating AHR, mucus hypersecretion, eotaxin production, and eosinophilia in the allergic lung. Moreover, IL-13+/+ T cells induce these features (except mucus production) of allergic disease independently of the IL-4Rα chain. By contrast, IL-13+/+ T cells did not induce disease in STAT6-deficient mice. This shows that IL-13 employs a novel component of the IL-13 receptor signaling system that involves STAT6, independently of the IL-4Rα chain, to modulate pathogenesis. We show that this novel pathway for IL-13 signaling is dependent on T cell activation in the lung and is critically linked to downstream effector pathways regulated by eotaxin and STAT6.
142 citations
TL;DR: It is suggested that human recombinant IL-13, but not IL-4, can induce differentiation into mature goblet cells that produce MUC5AC protein in guinea pig tracheal epithelial cells in vitro.
Abstract: The Th2 cytokines, interleukin (IL)-4 and IL-13, bind to IL-4R, that IL-4 inhibited mucus secretion and attenuated the gene and cause goblet cell metaplasia/hyperplasia with increased expression of MUC5AC and MUC5B in primary human mucin expression in vivo. However, there is not enough evi- bronchial epithelial cells (8), and that IL-4 did not induce dence that these cytokines directly induce mucin production in MUC5AC gene expression in mucoepidermoid carcinoma vitro. In this study, primary epithelial cells from guinea pig cell line, NCI-H292 (9). Concerning IL-13, Longphre and cotrachea were cultured at an air–liquid interface, and immedi- workers (10) reported that IL-13 did not increase MUC5AC ately after achieving confluence at Day 7 they were treated gene expression in NCI-H292 cells, but it is uncertain with human recombinant IL-4 or IL-13 for 14 d. IL-13–treated whether IL-13 induces mucin production and MUC5AC cells consisted of a large number of fully mature goblet cells expression in primary culture of lower airway epithelium. with a smaller number of ciliated cells. Secretory granules of the goblet cells were positive for both periodic acid-Schiff and We studied the effects of IL-4 and IL-13 on airway epitoluidine blue, and showed exocytosis. By contrast, IL-4 failed thelial differentiation using air–liquid interface culture, a to induce goblet cell differentiation. The electric resistances of procedure that induces high levels of differentiation (11–13), IL-13–treated cells were lower than those of IL-4–treated cells with airway epithelial cells differentiating into both ciliated and nontreated cells, suggesting leaky epithelia. MUC5AC pro- and goblet cells. In this study, we focused on the numbers of tein level in cell lysates measured by ELISA was several-fold goblet cells and ciliated cells, because goblet cell hyperplasia higher in IL-13–treated cells than in nontreated cells, whereas along with correspondingly fewer ciliated cells may cause the level in IL-4–treated cells was not changed. These data the impairment of mucociliary clearance that is found in suggest that human recombinant IL-13, but not IL-4, can induce the airways of patients who die of asthma (14). We also
141 citations
References
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Journal Article•
TL;DR: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished.
Abstract: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.
7,567 citations
"Induction of Airway Mucus Productio..." refers background in this paper
...The lower limit of sensitivity for each of the ELISAs was 0.6 ng/ml (IFNg ), 5 pg/ml (IL-4), 0.010 ng/ml (IL-5), and 200 pg/ml (IL-10)....
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...CD4 Th2 cells make a different panel of cytokines, including IL-4, IL-5, and IL-10 (17, 18)....
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...Assays were standardized with recombinant IFNg , IL-5, IL-10 (Endogen), and IL-4 (Collaborative Research, Inc.)....
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...1 A ), and IL-10 (data not shown)....
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...IL-4 2/2 OVA-specific Th2 cells produced comparable levels of IL-5 and IL-10 when compared to IL-4 1/1 OVA-specific Th2 cells, but IL-4 was produced only by IL-4 1/1 Th2 cells....
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TL;DR: Atopic asthma is associated with activation in the bronchi of the interleukin-3, 4, and 5 and GM-CSF gene cluster, a pattern compatible with predominant activation of the TH2-like T-cell population.
Abstract: Background. In atopic asthma, activated T helper lymphocytes are present in bronchial-biopsy specimens and bronchoalveolar-lavage (BAL) fluid, and their production of cytokines may be important in the pathogenesis of this disorder. Different patterns of cytokine release are characteristic of certain subgroups of T helper cells, termed TH1 and TH2, the former mediating delayed-type hypersensitivity and the latter mediating IgE synthesis and eosinophilia. The pattern of cytokine production in atopic asthma is unknown. Methods. We assessed cells obtained by BAL in subjects with mild atopic asthma and in normal control subjects for the expression of messenger RNA (mRNA) for interleukin-2, 3, 4, and 5, granulocytemacrophage colony-stimulating factor (GM-CSF), and interferon gamma by in situ hybridization with 32P-labeled complementary RNA. Localization of mRNA to BAL T cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or...
2,898 citations
"Induction of Airway Mucus Productio..." refers background in this paper
...Th2 cells secreting IL-4 and IL-5 have been shown to be present and activated in the bronchial wall of asthmatic individuals (9, 23)....
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TL;DR: This paper used hybridoma monoclonal antibodies obtained after immunization of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes.
Abstract: Xenogeneic immunizations have the advantage of detecting a wide range of antigenic determinants because many commonly occurring proteins have diverged significantly during the course of evolution and are thus antigenic in other species. The broadness of xenogeneic responses, however, means that the antisera they produce are usually complex and require extensive absorptions to make them specific for a single antigen. This problem has now been overcome by generating hybridomas producing monoclonal antibodies (Kohler & Milstein 1975). These permit dissection ofthe xenogeneic response so that large amounts of individual antibodies can be obtained, each of which recognizes only one of the determinants recognized by a broadly reactive conventional antiserum. Williams et al. (1977) used hybridoma monoclonal antibodies obtained after immunizations of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes, i.e., differentiation antigens. Springer et al. (1978a) and Stern et al. (1978) used a similar approach to study mouse lymphocyte antigens. They prepared monoclonal antibodies by immunizing rats with mouse lymphocytes and showed that these monoclonals recognized previously undetected mouse cell surface determinants including a glycoprotein antigen that appears to be specific for macrophages (Springer et al. 1978b). Trowbridge (1978) also used rat anti-mouse immunizations to generate a monoclonal antibody against the non-polymorphic lymphocyte surface antigen T200.
1,916 citations
"Induction of Airway Mucus Productio..." refers methods in this paper
...To generate Th1 or Th2 cells from DO11.10 mice, CD4 T cells were isolated by negative selection as previously described (31) using mAbs to CD8 (clone 53-6.72, clone 2.43 [ 32 ]), Class II MHC I-A d (212.A1 [33]) and anti‐Ig-coated magnetic beads (Advanced Magnetics, Inc....
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TL;DR: Results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance in mice transgenic for a T cell receptor that reacts to this peptide.
Abstract: In order to examine the mechanisms by which clonal deletion of autoreactive T cells occurs, a peptide antigen was used to induce deletion of antigen-reactive thymocytes in vivo. Mice transgenic for a T cell receptor (TCR) that reacts to this peptide contain thymocytes that progress from the immature to the mature phenotype. Intraperitoneal administration of the peptide antigen to transgenic mice results in a rapid deletion of the immature CD4+ CD8+ TCRlo thymocytes. Apoptosis of cortical thymocytes can be seen within 20 hours of treatment. These results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance.
1,831 citations
TL;DR: Some but not all of the in vitro properties of IL-4 are critical for the physiology of the immune system in vivo, but the serum levels of IgG1 and IgE are strongly reduced.
Abstract: Interleukin-4 (IL-4) promotes the growth and differentiation of many hematopoietic cells in vitro; in particular, it directs the immunoglobulin (Ig) class switch to IgG1 and IgE. Mice homozygous for a mutation that inactivates the IL-4 gene were generated to test the requirement for IL-4 in vivo. In the mutant mice T and B cell development was normal, but the serum levels of IgG1 and IgE were strongly reduced. The IgG1 dominance in a T cell-dependent immune response was lost, and IgE was not detectable upon nematode infection. Thus, some but not all of the in vitro properties of IL-4 are critical for the physiology of the immune system in vivo.
1,262 citations