Abstract
Human filarial parasites cause chronic infection associated with long-term down-regulation of the host's immune response. We show here that CD4+ T cell regulation is the main determinant of parasite survival. In a laboratory model of infection, using Litomosoides sigmodontis in BALB/c mice, parasites establish for >60 days in the thoracic cavity. During infection, CD4+ T cells at this site express increasing levels of CD25, CTLA-4, and glucocorticoid-induced TNF receptor family-related gene (GITR), and by day 60, up to 70% are CTLA-4(+)GITR(high), with a lesser fraction coexpressing CD25. Upon Ag stimulation, CD4(+)CTLA-4(+)GITR(high) cells are hyporesponsive for proliferation and cytokine production. To test the hypothesis that regulatory T cell activity maintains hyporesponsiveness and prolongs infection, we treated mice with Abs to CD25 and GITR. Combined Ab treatment was able to overcome an established infection, resulting in a 73% reduction in parasite numbers (p < 0.01). Parasite killing was accompanied by increased Ag-specific immune responses and markedly reduced levels of CTLA-4 expression. The action of the CD25(+)GITR+ cells was IL-10 independent as in vivo neutralization of IL-10R did not restore the ability of the immune system to kill parasites. These data suggest that regulatory T cells act, in an IL-10-independent manner, to suppress host immunity to filariasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antigens, CD
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Antigens, Differentiation / metabolism
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Antilymphocyte Serum / administration & dosage
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / pathology
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CTLA-4 Antigen
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Cell Proliferation
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DNA-Binding Proteins / genetics
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Disease Models, Animal
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Female
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Filariasis / genetics
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Filariasis / immunology*
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Filariasis / parasitology
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Filarioidea / immunology*
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Filarioidea / isolation & purification
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Filarioidea / pathogenicity
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Forkhead Transcription Factors
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Gene Expression
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Glucocorticoid-Induced TNFR-Related Protein
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Humans
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In Vitro Techniques
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Interleukin-10 / biosynthesis
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Lymphocyte Activation
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Lymphocyte Depletion
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Mice
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Mice, Inbred BALB C
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Receptors, Interleukin-2 / metabolism
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Receptors, Nerve Growth Factor / metabolism
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Receptors, Tumor Necrosis Factor / metabolism
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Th1 Cells / immunology
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Th2 Cells / immunology
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Transforming Growth Factor beta / biosynthesis
Substances
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Antibodies, Monoclonal
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Antigens, CD
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Antigens, Differentiation
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Antilymphocyte Serum
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CTLA-4 Antigen
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CTLA4 protein, human
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Ctla4 protein, mouse
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DNA-Binding Proteins
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FOXP3 protein, human
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Glucocorticoid-Induced TNFR-Related Protein
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Receptors, Interleukin-2
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Receptors, Nerve Growth Factor
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Receptors, Tumor Necrosis Factor
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Tnfrsf18 protein, mouse
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Transforming Growth Factor beta
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Interleukin-10