Abstract
In a recent study, we found that TNF-alpha negatively regulates airway responsiveness through the activation of gammadelta T cells. The biological activities of TNF-alpha are mediated by two structurally related but functionally distinct receptors, p55 (TNFR1) and p75 (TNFR2), which are independently expressed on the cell surface. However, the relative importance of either TNFR in airway hyperresponsiveness (AHR) is unknown. To investigate the importance of these TNFRs in the development of allergen-induced AHR, p55-deficient and p75-deficient mice were sensitized to OVA by i.p. injection and subsequently challenged with OVA via the airways; airway responsiveness to inhaled methacholine was monitored. p75-deficient mice developed AHR to a similar degree as control mice. In contrast, p55-deficient mice, which were sensitized and challenged with OVA, failed to develop AHR. In p55-deficient mice, both the numbers of eosinophils and levels of IL-5 in bronchoalveolar lavage fluid were significantly lower than in sensitized/challenged control mice (p < 0.05). However, depletion of gammadelta T cells resulted in significant increases in AHR in the p55-deficient mice, whereas no significant effect of gammadelta T cell depletion was evident in the p75-deficient mice. These data indicate that, in the absence of TNFR1 (p55), where TNF-alpha uses the p75 pathway exclusively, the development of AHR is regulated by gammadelta T cells.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antigens, CD / genetics
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Antigens, CD / physiology*
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Bronchial Hyperreactivity / genetics
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Bronchial Hyperreactivity / immunology*
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Bronchial Hyperreactivity / pathology
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Bronchial Hyperreactivity / prevention & control
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Bronchoalveolar Lavage Fluid / chemistry
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Bronchoalveolar Lavage Fluid / cytology
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Bronchoalveolar Lavage Fluid / immunology
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Cytokines / biosynthesis
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Female
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Genetic Predisposition to Disease
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Immunoglobulin E / biosynthesis
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Inflammation / immunology
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Inflammation / pathology
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Injections, Intraperitoneal
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Injections, Intravenous
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Lymphocyte Depletion
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Ovalbumin / administration & dosage
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Ovalbumin / immunology
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Receptors, Antigen, T-Cell, alpha-beta / analysis
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Receptors, Antigen, T-Cell, gamma-delta / analysis
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Receptors, Antigen, T-Cell, gamma-delta / immunology
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Receptors, Antigen, T-Cell, gamma-delta / physiology*
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Receptors, Tumor Necrosis Factor / deficiency
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / physiology*
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Cytokines
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Antigen, T-Cell, gamma-delta
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Immunoglobulin E
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Ovalbumin