Abstract
Independent studies have shown that CD27, 4-1BB, and OX40 can all promote survival of activated CD8+ T cells. We have therefore compared their impact on CD8+ memory T cell formation and responsiveness within one, physiologically relevant model system. Recombinant mice, selectively lacking input of one or two receptors, were challenged intranasally with influenza virus, and the immunodominant virus-specific CD8+ T cell response was quantified at priming and effector sites. Upon primary infection, CD27 and (to a lesser extent) 4-1BB made nonredundant contributions to accumulation of CD8+ virus-specific T cells in draining lymph nodes and lung, while OX40 had no effect. Interestingly though, in the memory response, accumulation of virus-specific CD8+ T cells in spleen and lung critically depended on all three receptor systems. This was explained by two observations: 1) CD27, 4-1BB, and OX40 were collectively responsible for generation of the same memory CD8+ T cell pool; 2) CD27, 4-1BB, and OX40 collectively determined the extent of secondary expansion, as shown by adoptive transfers with standardized numbers of memory cells. Surprisingly, wild-type CD8+ memory T cells expanded normally in primed OX40 ligand- or 4-1BB ligand-deficient mice. However, when wild-type memory cells were generated in OX40 ligand- or 4-1BB ligand-deficient mice, their secondary expansion was impaired. This provides the novel concept that stimulation of CD8+ T cells by OX40 and 4-1BB ligand during priming imprints into them the capacity for secondary expansion. Our data argue that ligand on dendritic cells and/or B cells may be critical for this.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Intranasal
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Adoptive Transfer
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Animals
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Antibodies, Viral / biosynthesis
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Antigen-Presenting Cells / immunology
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Antigen-Presenting Cells / metabolism
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Antigen-Presenting Cells / virology
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Antigens, CD / biosynthesis
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Antigens, CD / genetics
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Antigens, CD / physiology*
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CD8-Positive T-Lymphocytes / cytology*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / virology
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Cell Proliferation*
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Genomic Imprinting
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Immunization, Secondary
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Immunologic Memory* / genetics
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Influenza A virus / immunology
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Ligands
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Lymphocyte Activation / genetics
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology
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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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Orthomyxoviridae Infections / genetics
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Orthomyxoviridae Infections / immunology*
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Orthomyxoviridae Infections / virology
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Receptors, Nerve Growth Factor / biosynthesis
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Receptors, Nerve Growth Factor / deficiency
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Receptors, Nerve Growth Factor / genetics
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Receptors, Nerve Growth Factor / physiology*
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Receptors, OX40
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor / deficiency
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / physiology*
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / transplantation
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T-Lymphocyte Subsets / virology
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / biosynthesis
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / physiology*
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Tumor Necrosis Factors
Substances
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Antibodies, Viral
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Antigens, CD
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Ligands
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Membrane Glycoproteins
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OX40 Ligand
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Receptors, Nerve Growth Factor
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Receptors, OX40
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Receptors, Tumor Necrosis Factor
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Tnfrsf4 protein, mouse
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Tnfrsf9 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 Factor Receptor Superfamily, Member 9
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Tumor Necrosis Factors