Abstract
CD4(+)25(+) regulatory T (Treg) cells maintain immunological self-tolerance through mechanisms that are only in part understood. Previous studies suggest that the glucocorticoid-induced TNFR-related protein (GITR), which is preferentially expressed on the surface of Treg cells, potentially provides a signal that abrogates Treg suppression. In this study, we show that a soluble form of mouse GITR ligand (sGITR-L) induces GITR-dependent NF-kappaB activation and blocks in vitro suppression mediated by both resting and preactivated polyclonal and Ag-specific Treg cells. Since sGITR-L along with rIL-2 induces proliferation of CD4(+)25(+) cells, it appears that sGITR-L can break the anergic state of Treg cells. Because sGITR-L also up-regulates IL-2 secretion by activated CD4(+)25 (-)T cells, these two sGITR-L induced signals synergize to interfere with suppressor activity by CD4(+)25(+) Treg cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / metabolism
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Adjuvants, Immunologic / physiology*
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Animals
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Carrier Proteins / metabolism
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Carrier Proteins / physiology*
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Cell Division / immunology
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Cell Line
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Clonal Anergy / immunology*
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Glucocorticoid-Induced TNFR-Related Protein
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Humans
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Interleukin-2 / metabolism
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Interleukin-2 / physiology
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Interphase / immunology
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Ligands
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Mice
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Mice, Inbred BALB C
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NF-kappa B / metabolism
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NF-kappa B / physiology
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Receptors, Interleukin-2 / biosynthesis
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Receptors, Nerve Growth Factor / metabolism*
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction / immunology
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Solubility
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocytes, Regulatory / cytology*
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Tumor Necrosis Factors
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Up-Regulation / immunology
Substances
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Adjuvants, Immunologic
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Carrier Proteins
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Glucocorticoid-Induced TNFR-Related Protein
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Interleukin-2
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Ligands
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NF-kappa B
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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, human
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Tnfrsf18 protein, mouse
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Tnfsf18 protein, mouse
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Tumor Necrosis Factors