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PMID:23589618

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Citation

Ammann, JU, Cooke, A and Trowsdale, J (2013) Butyrophilin Btn2a2 inhibits TCR activation and phosphatidylinositol 3-kinase/Akt pathway signaling and induces Foxp3 expression in T lymphocytes. J. Immunol. 190:5030-6

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.

Links

PubMed PMC3736090 Online version:10.4049/jimmunol.1203325

Keywords

Animals; Antigens, CD28/immunology; Antigens, CD3/immunology; Antigens, CD4/immunology; Apoptosis; B-Lymphocytes/metabolism; CD4-Positive T-Lymphocytes/immunology; CD4-Positive T-Lymphocytes/metabolism; Cell Cycle/drug effects; Cell Proliferation/drug effects; Cells, Cultured; Dendritic Cells/metabolism; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors; Forkhead Transcription Factors/biosynthesis; Forkhead Transcription Factors/genetics; Interleukin-2 Receptor alpha Subunit/immunology; Lipopeptides; Lipopolysaccharides; Lymphocyte Activation/immunology; Macrophages/metabolism; Membrane Glycoproteins/metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Phosphatidylinositol 3-Kinase/antagonists & inhibitors; Phosphatidylinositol 3-Kinase/metabolism; Proto-Oncogene Proteins c-akt/antagonists & inhibitors; Proto-Oncogene Proteins c-akt/metabolism; Receptors, Antigen, T-Cell/antagonists & inhibitors; Signal Transduction/immunology; ZAP-70 Protein-Tyrosine Kinase/antagonists & inhibitors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:BT2A2

acts_upstream_of_or_within

GO:0014067: negative regulation of phosphatidylinositol 3-kinase signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:88327

P

  • regulates_o_occurs_in:(CL:0000084)

Seeded From UniProt

complete

MOUSE:BT2A2

located_in

GO:0009986: cell surface

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000785)|part_of:(CL:0000451)|part_of:(CL:0000581)

Seeded From UniProt

complete

MOUSE:BT2A2

acts_upstream_of_or_within

GO:0051898: negative regulation of protein kinase B signaling

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:88327

P

  • regulates_o_occurs_in:(CL:0000084)

Seeded From UniProt

complete

MOUSE:BT2A2

acts_upstream_of_or_within

GO:0050860: negative regulation of T cell receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BT2A2

acts_upstream_of_or_within

GO:0046007: negative regulation of activated T cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BT2A2

acts_upstream_of_or_within

GO:0045591: positive regulation of regulatory T cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BT2A2

acts_upstream_of_or_within

GO:2000134: negative regulation of G1/S transition of mitotic cell cycle

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000084)

Seeded From UniProt

complete

MOUSE:BT2A2

acts_upstream_of_or_within

GO:0070373: negative regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000084)

Seeded From UniProt

complete

MOUSE:CD28

acts_upstream_of_or_within

GO:0014068: positive regulation of phosphatidylinositol 3-kinase signaling

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000084)

Seeded From UniProt

complete

MOUSE:CD28

acts_upstream_of_or_within

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000084)

Seeded From UniProt

complete

MOUSE:CD28

acts_upstream_of_or_within

GO:0014068: positive regulation of phosphatidylinositol 3-kinase signaling

ECO:0000314: direct assay evidence used in manual assertion

P

regulates_o_occurs_in:(CL:0000084)

Seeded From UniProt

complete

MOUSE:CD28

acts_upstream_of_or_within

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

regulates_o_occurs_in:(CL:0000084)

Seeded From UniProt

complete

Notes

See also

References

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