Abstract
CD28 signals contribute to either type 1 or type 2 T cell differentiation. Here, we show that administration of B7.2-Ig fusion proteins to tumor-bearing mice induces tumor regression by promoting the differentiation of antitumor type 2 CD8(+) effector T cells along with IL-4 production. B7.2-Ig-mediated regression was not induced in IL-4(-/-) and STAT6(-/-) mice. However, it was elicited in IFN-gamma(-/-) and STAT4(-/-) mice. By contrast, IL-12-induced tumor regression occurred in IL-4(-/-) and STAT6(-/-) mice, but not in IFN-gamma(-/-) and STAT4(-/-) mice. Moreover, B7.2-Ig treatment was effective in a tumor model not responsive to IL-12. B7.2-Ig administration elicited elevated levels of IL-4 production. Tumor regression was predominantly mediated by CD8(+) T cells, although the induction of these effector cells required CD4(+) T cells. Tumor regression induced by CD8(+) T cells alone was inhibited by neutralizing the IL-4 produced during B7.2-Ig treatment. Thus, these results indicate that stimulation in vivo of CD28 with B7.2-Ig in tumor-bearing mice results in enhanced induction of antitumor type 2 CD8(+) T cells (Tc2) leading to Tc2-mediated tumor regression.
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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Animals
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Antibodies, Monoclonal / administration & dosage
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Antigens, CD / administration & dosage*
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Antigens, CD / genetics
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Antigens, CD / therapeutic use
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B7-2 Antigen
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CD4-Positive T-Lymphocytes / immunology
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Cell Line, Tumor
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Cytotoxicity, Immunologic
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Female
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Fibrosarcoma / immunology*
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Fibrosarcoma / pathology
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Fibrosarcoma / prevention & control*
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Immunoglobulin Fc Fragments / administration & dosage*
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Immunoglobulin Fc Fragments / genetics
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Immunoglobulin Fc Fragments / therapeutic use
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Inducible T-Cell Co-Stimulator Ligand
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Injections, Subcutaneous
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Interleukin-12 / administration & dosage
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Interleukin-4 / biosynthesis*
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Interleukin-4 / deficiency
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Interleukin-4 / immunology
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Interleukin-4 / physiology
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Male
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Membrane Glycoproteins / administration & dosage*
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / therapeutic use
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Proteins / administration & dosage
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Proteins / genetics
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Recombinant Fusion Proteins / administration & dosage*
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Recombinant Fusion Proteins / therapeutic use
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Remission Induction
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Regulatory / immunology*
Substances
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Antibodies, Monoclonal
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Antigens, CD
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B7-2 Antigen
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Cd86 protein, mouse
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Icosl protein, mouse
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Immunoglobulin Fc Fragments
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Inducible T-Cell Co-Stimulator Ligand
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Membrane Glycoproteins
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Proteins
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Recombinant Fusion Proteins
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Interleukin-12
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Interleukin-4