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Induction of airway mucus production By T helper 2 (Th2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production.

Cohn L, Homer RJ, Marinov A, Rankin J, Bottomly K - J. Exp. Med. (1997)

Bottom Line: When this defect in homing was overcome by administration of TNF-alpha, 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. lcohn@biomed.med.yale.edu

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-alpha, 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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Immunohistochemical analysis of lungs from mice  that received transfer of  DO11.10 TCR transgenic cells.  Localization in the lung of CD4  and donor TCR transgenic cells  (A, B). Sequential lung sections  from mice that received Th1  cells and exposure to aerosolized  OVA were stained with (A) anti-CD4 and (B) KJ1-26 antibodies.  KJ1-26 recognizes the DO11.10  TCR and was present on >99%  of Th1 cells at the time of transfer. An airway and small vessel  are shown with surrounding inflammatory cells (100×). A majority of the infiltrating cells stain  positively for both CD4 and the  transgenic TCR. (C, D) MHC  Class II expression in the lung after transfer of Th1 or Th2 cells.  Lung sections from mice that received (C) Th1 or (D) Th2 cells  and exposure to inhaled OVA  were stained with an anti–I-A  antibody (212.A1). A small  bronchiole is shown. Both mice  that received transfer of Th1 or Th2 cells and aerosolized OVA exhibited increased MHC Class II expression on cells in the inflammatory infiltrates (red-stained cells) (200×). Mice that received transfer of Th1 cells had increased red-staining of bronchial epithelium, whereas mice that received Th2 cells  had no evidence of Class II MHC expression on bronchial epithelial cells.
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Figure 4: Immunohistochemical analysis of lungs from mice that received transfer of DO11.10 TCR transgenic cells. Localization in the lung of CD4 and donor TCR transgenic cells (A, B). Sequential lung sections from mice that received Th1 cells and exposure to aerosolized OVA were stained with (A) anti-CD4 and (B) KJ1-26 antibodies. KJ1-26 recognizes the DO11.10 TCR and was present on >99% of Th1 cells at the time of transfer. An airway and small vessel are shown with surrounding inflammatory cells (100×). A majority of the infiltrating cells stain positively for both CD4 and the transgenic TCR. (C, D) MHC Class II expression in the lung after transfer of Th1 or Th2 cells. Lung sections from mice that received (C) Th1 or (D) Th2 cells and exposure to inhaled OVA were stained with an anti–I-A antibody (212.A1). A small bronchiole is shown. Both mice that received transfer of Th1 or Th2 cells and aerosolized OVA exhibited increased MHC Class II expression on cells in the inflammatory infiltrates (red-stained cells) (200×). Mice that received transfer of Th1 cells had increased red-staining of bronchial epithelium, whereas mice that received Th2 cells had no evidence of Class II MHC expression on bronchial epithelial cells.

Mentions: To investigate how different effector CD4 T cells influence inflammation in the respiratory tract, mice that received Th1, Th2, or unprimed naive CD4 T cells were compared. Mice that received Th1 or Th2 cells and were exposed to aerosolized OVA had moderate inflammation in the respiratory tract (Fig. 2, A1 and B1). The lungs from both groups of mice showed inflammation in a predominantly peribronchial and perivascular pattern. Despite similar degrees of inflammation, the two groups of mice had strikingly different inflammatory processes as determined by lung histology and analysis of BAL cells. The inflammatory infiltrates in the lungs of mice that received Th1 cells consisted of neutrophils, small mononuclear cells and macrophages (Fig. 2 B1). Differential counts performed on cells recovered from BAL confirmed these findings (Fig. 3). Immunohistochemical analysis of lung tissue showed that many infiltrating inflammatory cells stained with an anti-CD4 antibody (Fig. 4 A), the majority of these cells also stained with the TCR anticlonotypic antibody, KJ1-26 (Fig. 4 B). MHC Class II expression in the lungs of these mice was increased on bronchial epithelial cells (Fig. 4 C) when compared to mice that received Th2 cells (Fig. 4 D), as expected from the effects of IFN-γ on airway epithelial cells (42).


Induction of airway mucus production By T helper 2 (Th2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production.

Cohn L, Homer RJ, Marinov A, Rankin J, Bottomly K - J. Exp. Med. (1997)

Immunohistochemical analysis of lungs from mice  that received transfer of  DO11.10 TCR transgenic cells.  Localization in the lung of CD4  and donor TCR transgenic cells  (A, B). Sequential lung sections  from mice that received Th1  cells and exposure to aerosolized  OVA were stained with (A) anti-CD4 and (B) KJ1-26 antibodies.  KJ1-26 recognizes the DO11.10  TCR and was present on >99%  of Th1 cells at the time of transfer. An airway and small vessel  are shown with surrounding inflammatory cells (100×). A majority of the infiltrating cells stain  positively for both CD4 and the  transgenic TCR. (C, D) MHC  Class II expression in the lung after transfer of Th1 or Th2 cells.  Lung sections from mice that received (C) Th1 or (D) Th2 cells  and exposure to inhaled OVA  were stained with an anti–I-A  antibody (212.A1). A small  bronchiole is shown. Both mice  that received transfer of Th1 or Th2 cells and aerosolized OVA exhibited increased MHC Class II expression on cells in the inflammatory infiltrates (red-stained cells) (200×). Mice that received transfer of Th1 cells had increased red-staining of bronchial epithelium, whereas mice that received Th2 cells  had no evidence of Class II MHC expression on bronchial epithelial cells.
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Related In: Results  -  Collection

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Figure 4: Immunohistochemical analysis of lungs from mice that received transfer of DO11.10 TCR transgenic cells. Localization in the lung of CD4 and donor TCR transgenic cells (A, B). Sequential lung sections from mice that received Th1 cells and exposure to aerosolized OVA were stained with (A) anti-CD4 and (B) KJ1-26 antibodies. KJ1-26 recognizes the DO11.10 TCR and was present on >99% of Th1 cells at the time of transfer. An airway and small vessel are shown with surrounding inflammatory cells (100×). A majority of the infiltrating cells stain positively for both CD4 and the transgenic TCR. (C, D) MHC Class II expression in the lung after transfer of Th1 or Th2 cells. Lung sections from mice that received (C) Th1 or (D) Th2 cells and exposure to inhaled OVA were stained with an anti–I-A antibody (212.A1). A small bronchiole is shown. Both mice that received transfer of Th1 or Th2 cells and aerosolized OVA exhibited increased MHC Class II expression on cells in the inflammatory infiltrates (red-stained cells) (200×). Mice that received transfer of Th1 cells had increased red-staining of bronchial epithelium, whereas mice that received Th2 cells had no evidence of Class II MHC expression on bronchial epithelial cells.
Mentions: To investigate how different effector CD4 T cells influence inflammation in the respiratory tract, mice that received Th1, Th2, or unprimed naive CD4 T cells were compared. Mice that received Th1 or Th2 cells and were exposed to aerosolized OVA had moderate inflammation in the respiratory tract (Fig. 2, A1 and B1). The lungs from both groups of mice showed inflammation in a predominantly peribronchial and perivascular pattern. Despite similar degrees of inflammation, the two groups of mice had strikingly different inflammatory processes as determined by lung histology and analysis of BAL cells. The inflammatory infiltrates in the lungs of mice that received Th1 cells consisted of neutrophils, small mononuclear cells and macrophages (Fig. 2 B1). Differential counts performed on cells recovered from BAL confirmed these findings (Fig. 3). Immunohistochemical analysis of lung tissue showed that many infiltrating inflammatory cells stained with an anti-CD4 antibody (Fig. 4 A), the majority of these cells also stained with the TCR anticlonotypic antibody, KJ1-26 (Fig. 4 B). MHC Class II expression in the lungs of these mice was increased on bronchial epithelial cells (Fig. 4 C) when compared to mice that received Th2 cells (Fig. 4 D), as expected from the effects of IFN-γ on airway epithelial cells (42).

Bottom Line: When this defect in homing was overcome by administration of TNF-alpha, 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.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. lcohn@biomed.med.yale.edu

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-alpha, 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.

Show MeSH
Related in: MedlinePlus