Abstract
Mice deficient in OX40 or 4-1BB costimulatory pathways show defects in T cell recall responses, with predominant effects on CD4 vs CD8 T cells, respectively. However, OX40L can also stimulate CD8 T cells and 4-1BBL can influence CD4 T cells, raising the possibility of redundancy between the two TNFR family costimulators. To test this possibility, we generated mice deficient in both 4-1BBL and OX40L. In an adoptive transfer model, CD4 T cells expressed 4-1BB and OX40 sequentially in response to immunization, with little or no overlap in the timing of their expression. Under the same conditions, CD8 T cells expressed 4-1BB, but no detectable OX40. Thus, in vivo expression of 4-1BB and OX40 can be temporally and spatially segregated. In the absence of OX40L, there were decreased CD4 T cells late in the primary response and no detectable secondary expansion of adoptively transferred CD4 T cells under conditions in which primary expansion was unaffected. The 4-1BBL had a minor effect on the primary response of CD4 T cells in this model, but showed larger effects on the secondary response, although 4-1BBL(-/-) mice show less impairment in CD4 secondary responses than OX40L(-/-) mice. The 4-1BBL(-/-) and double knockout mice were similarly impaired in the CD8 T cell response, whereas OX40L(-/-) and double knockout mice were similarly impaired in the CD4 T cell response to both protein Ag and influenza virus. Thus, 4-1BB and OX40 act independently and nonredundantly to facilitate robust CD4 and CD8 recall responses.
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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4-1BB Ligand
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Adoptive Transfer / methods
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Animals
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Antigens, CD
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / microbiology
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CD4-Positive T-Lymphocytes / transplantation
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CD4-Positive T-Lymphocytes / virology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / microbiology
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CD8-Positive T-Lymphocytes / transplantation
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CD8-Positive T-Lymphocytes / virology
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Cell Proliferation
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Enterotoxins / administration & dosage
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Enterotoxins / immunology
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Epitopes, T-Lymphocyte / immunology
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Immunization, Secondary / methods
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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 / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism
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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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Mice, Transgenic
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OX40 Ligand
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Receptors, Nerve Growth Factor / biosynthesis
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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 / physiology*
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Superantigens / administration & dosage
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Superantigens / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Tumor Necrosis Factor-alpha / deficiency
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / physiology
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Tumor Necrosis Factors
Substances
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4-1BB Ligand
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Antigens, CD
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Enterotoxins
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Epitopes, T-Lymphocyte
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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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Superantigens
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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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Tnfsf9 protein, mouse
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Tumor Necrosis Factor-alpha
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Tumor Necrosis Factors
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enterotoxin A, Staphylococcal