Abstract
The butyrophilin-related protein Btn2a2 was upregulated on murine APC including CD19(+) B cells, CD11b(+)F4/80(+) peritoneal macrophages, and CD11c(+) bone marrow-derived dendritic cells after activation with LPS or Pam3CysK4, suggesting a role in modulation of T lymphocytes. Consistent with this, binding of mouse Btn2a2-Fc to CD3(+) primary mouse T cells stimulated with anti-CD3 and anti-CD28 reduced the number of proliferating cells and entry of cells into the cell cycle. Binding of Btn2a2-Fc to anti-CD3-stimulated T cells inhibited CD3ε, Zap70, and subsequent Erk1/2 activation. It also interfered with activation of the regulatory subunit of PI3K, p85, and activation of Akt in T cells stimulated with both anti-CD3 and anti-CD28. Inhibition of Akt activation by Btn2a2-Fc was, in contrast to inhibition by programmed death ligand-1-Fc, not overcome by anti-CD28 costimulation. Using Foxp3-GFP-transgenic, naive T cells, Btn2a2-Fc induced de novo expression of Foxp3 in a dose-dependent manner, and Btn2a2-Fc-induced CD4(+)CD25(+)Foxp3(+) T cells had inhibitory properties. The data indicate an important physiological role for Btn2a2 in inhibiting T cell activation and inducing Foxp3(+) regulatory T cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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B-Lymphocytes / metabolism
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Butyrophilins
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CD28 Antigens / immunology
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CD3 Complex / immunology
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CD4 Antigens / immunology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cell Cycle / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Dendritic Cells / metabolism
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Forkhead Transcription Factors / biosynthesis*
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Forkhead Transcription Factors / genetics
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Interleukin-2 Receptor alpha Subunit / immunology
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Lipopeptides
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Lipopolysaccharides
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Lymphocyte Activation / immunology
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Macrophages / metabolism
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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Mice, Transgenic
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Phosphatidylinositol 3-Kinase / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Antigen, T-Cell / antagonists & inhibitors
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Signal Transduction / immunology
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ZAP-70 Protein-Tyrosine Kinase / antagonists & inhibitors
Substances
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Butyrophilins
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CD28 Antigens
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CD3 Complex
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CD4 Antigens
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2 Receptor alpha Subunit
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Lipopeptides
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Lipopolysaccharides
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Membrane Glycoproteins
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Pam(3)CSK(4) peptide
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Antigen, T-Cell
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Phosphatidylinositol 3-Kinase
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ZAP-70 Protein-Tyrosine Kinase
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Zap70 protein, mouse
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases