Abstract
The engagement of CD137 (4-1BB), an inducible T cell costimulatory receptor and member of the TNF receptor superfamily, by agonistic Abs can promote strong tumor and viral immunity mediated by CD8(+) T cells and stimulate IFN-gamma production. However, its role in Th2-mediated immune responses has not been well defined. To address this issue, we studied the function of CD137 engagement using an allergic airway disease model in which the mice were sensitized with inactivated Schistosoma mansoni eggs followed by S. mansoni egg Ag challenge directly in the airways and Th1/2 cytokine production was monitored. Interestingly, treatment of C57BL/6 mice with agonistic anti-CD137 (2A) during sensitization completely prevents allergic airway inflammation, as shown by a clear inhibition of T cell and eosinophil infiltration into the lung tissue and airways, accompanied by diminished Th2 cytokine production and reduced serum IgE levels, as well as a reduction of airway hyperresponsiveness. At various time points after immunization, restimulated splenocytes from 2A-treated mice displayed reduced proliferation and Th2 cytokine production. In accordance with this, agonistic Ab to CD137 can directly coinhibit Th2 responses in vitro although it costimulates Th1 responses. CD137-mediated suppression of Th2 response is independent of IFN-gamma and T regulatory cells. Our study has identified a novel pathway to inhibit Th2 responses in a CD137-dependent fashion.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antigens, CD / immunology
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Antigens, CD / physiology*
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Antigens, Helminth / administration & dosage
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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 / immunology
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Cells, Cultured
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Down-Regulation / immunology*
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Female
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GATA3 Transcription Factor / antagonists & inhibitors
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GATA3 Transcription Factor / biosynthesis
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GATA3 Transcription Factor / genetics
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Immunoglobulin E / biosynthesis
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Interferon-gamma / physiology
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Lung / immunology
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Lung / metabolism
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Lymphocyte Activation / immunology*
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Mice
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Mice, Inbred C57BL
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Receptors, Nerve Growth Factor / agonists
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Receptors, Nerve Growth Factor / immunology
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Receptors, Nerve Growth Factor / physiology*
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Receptors, Tumor Necrosis Factor / agonists
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Receptors, Tumor Necrosis Factor / immunology
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Receptors, Tumor Necrosis Factor / physiology*
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Schistosoma mansoni / immunology
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Schistosomiasis / immunology
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Schistosomiasis / pathology
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Schistosomiasis / prevention & control
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Signal Transduction / immunology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Th2 Cells / immunology*
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Th2 Cells / metabolism
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Tumor Necrosis Factor Receptor Superfamily, Member 9
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Helminth
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Receptors, Nerve Growth Factor
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Receptors, Tumor Necrosis Factor
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Tnfrsf9 protein, mouse
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Immunoglobulin E
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Interferon-gamma