title: Butyrophilin Btn2a2 inhibits TCR activation and phosphatidylinositol 3-kinase/Akt pathway signaling and induces Foxp3 expression in T lymphocytes.
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.
authors.affiliation: Division of Immunology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Johannes U
authors.initials: JU
authors.lastname: Ammann
authors.forename: Anne
authors.initials: A
authors.lastname: Cooke
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D000071797:Butyrophilins; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D055666:Lipopeptides; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000037:antagonists & inhibitors
chemical_list: D000071797:Butyrophilins; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D055666:Lipopeptides; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C508075:Pam(3)CSK(4) peptide; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; D058539:Phosphatidylinositol 3-Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases