Abstract
Aging is associated with an increased susceptibility to infectious agents and correlates with a decreased ability to mount an immune response. It has been postulated that the major defect is related to a reduced capacity of an aged T cell to proliferate and to survive after encounter with Ag. This is similar to the phenotype associated with T cell tolerance in young adults. In this study, we determined whether targeting 4-1BB (CD137), a member of the TNFR family implicated in providing expansion and survival signals to T cells, can rescue defective priming in aged and tolerized animals. Agonist Abs to 4-1BB injected in vivo were capable of preventing CD4 T cell tolerance to soluble peptide in young mice. Moreover, anti-4-1BB rescued defective priming of aged TCR transgenic CD4 T cells responding to peptide Ag in a young host, and as importantly, anti-4-1BB completely restored T cell priming to protein Ag in nontransgenic aged mice. These studies demonstrate that 4-1BB, and potentially other costimulatory members of the TNFR family, are targets for therapies aimed at augmenting weak T cell responses in elderly immunocompromised individuals.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adoptive Transfer
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Aging / genetics
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Aging / immunology*
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Animals
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Antigen-Presenting Cells / immunology
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Antigens, CD
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CD28 Antigens / physiology
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CD4-Positive T-Lymphocytes / immunology
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Cells, Cultured
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Chimera / immunology
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Cytochrome c Group / immunology
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Immune Sera / administration & dosage
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Immune Tolerance / genetics
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Injections, Intraperitoneal
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Moths / immunology
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Receptors, Nerve Growth Factor / agonists
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Receptors, Nerve Growth Factor / biosynthesis
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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 / biosynthesis
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Receptors, Tumor Necrosis Factor / immunology
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Receptors, Tumor Necrosis Factor / physiology*
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Solubility
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Tumor Necrosis Factor Receptor Superfamily, Member 9
Substances
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Antigens, CD
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CD28 Antigens
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Cytochrome c Group
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Immune Sera
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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