Abstract
Pulmonary eosinophilia induced in C57BL/6 mice after Cryptococcus neoformans infection is driven by CD4(+) Th2 cells. The immunological mechanisms that protect against eosinophilia are not fully understood. Interaction of OX40 (CD134) and its ligand, OX40L, has been implicated in T cell activation and cell migration. Unlike CD28, OX40 is only expressed on T cells 1-2 days after Ag activation. Manipulation of this pathway would therefore target recently activated T cells, leaving the naive repertoire unaffected. In this study, we show that engagement of OX40 by an OX40L:Ig fusion protein drives IFN-gamma production by CD4(+) T cells and reduces eosinophilia and C. neoformans burden in the lung. Using gene-depleted mice, we show that reduction of eosinophilia and pathogen burden requires IL-12 and/or IFN-gamma. C. neoformans infection itself only partially induces OX40L expression by APCs. Provision of exogenous OX40L reveals a critical role of this pathway in the prevention of C. neoformans-induced eosinophilia.
MeSH terms
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Adjuvants, Immunologic / administration & dosage
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Adjuvants, Immunologic / biosynthesis
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Adjuvants, Immunologic / metabolism*
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Adjuvants, Immunologic / physiology
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Animals
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Antigens, Differentiation / administration & dosage
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Antigens, Differentiation / metabolism
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Bronchi / immunology
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Bronchi / metabolism
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Bronchi / microbiology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / microbiology
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Cryptococcus neoformans / growth & development
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Cryptococcus neoformans / immunology*
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Down-Regulation / immunology*
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Eosinophils / immunology
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Eosinophils / pathology
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Female
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Injections, Intraperitoneal
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Interferon-gamma / biosynthesis
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Interferon-gamma / deficiency
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Interferon-gamma / genetics
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Interferon-gamma / physiology
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Ligands
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Lung / immunology
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Lung / metabolism
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Lung / microbiology
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Lymphocyte Activation / immunology*
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Membrane Glycoproteins / administration & dosage
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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OX40 Ligand
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Pulmonary Eosinophilia / genetics
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Pulmonary Eosinophilia / microbiology
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Pulmonary Eosinophilia / pathology
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Pulmonary Eosinophilia / prevention & control*
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Receptors, OX40
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Receptors, Tumor Necrosis Factor*
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / metabolism
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / microbiology*
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / administration & dosage
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / biosynthesis
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism*
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Tumor Necrosis Factors
Substances
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Adjuvants, Immunologic
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Antigens, Differentiation
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Ligands
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Membrane Glycoproteins
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OX40 Ligand
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OX40Ig
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Receptors, OX40
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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Tnfrsf4 protein, mouse
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Tnfsf4 protein, mouse
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Tumor Necrosis Factors
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Interferon-gamma