Abstract
The glucocorticoid-induced TNFR (GITR) is expressed at high levels on resting CD4(+)CD25(+) T regulatory (T(R)) cells and regulates their suppressive phenotype. Accordingly, we show that anti-GITR mAb treatment of SJL mice with proteolipid protein 139-151-induced experimental autoimmune encephalomyelitis significantly exacerbated clinical disease severity and CNS inflammation, and induced elevated levels of Ag-specific T cell proliferation and cytokine production. Interestingly, prior depletion of T(R) cells failed to result in exacerbated experimental autoimmune encephalomyelitis suggesting alternative targets for the anti-GITR mAb treatment. Importantly, naive CD4(+)CD25(-) T cells up-regulated GITR expression in an activation-dependent manner and anti-GITR mAb treatment enhanced the level of CD4(+) T cell activation, proliferation, and cytokine production in the absence of T(R) cells both in vivo and in vitro. Taken together, these findings suggest a dual functional role for GITR as GITR cross-linking both inactivates T(R) cells and increases CD4(+)CD25(-) T cell effector function, thus enhancing T cell immunity.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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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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Antibodies, Monoclonal / administration & dosage
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Autoantigens / immunology*
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism*
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Cell Division / immunology
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Cross-Linking Reagents / administration & dosage
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Cytokines / biosynthesis
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / mortality
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Glucocorticoids / physiology*
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Ligands
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Lymphocyte Activation / immunology*
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor / immunology*
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Receptors, Tumor Necrosis Factor / metabolism*
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Severity of Illness Index
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
Substances
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Adjuvants, Immunologic
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Antibodies, Monoclonal
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Autoantigens
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Cross-Linking Reagents
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Cytokines
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Glucocorticoids
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Ligands
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Receptors, Tumor Necrosis Factor