Pivotal advance: CEACAM1 is a negative coreceptor for the B cell receptor and promotes CD19-mediated adhesion of B cells in a PI3K-dependent manner.
Upon antigen binding, the BCR transduces a signal culminating in proliferation or in AICD of the B cell. Coreceptor engagement and subsequent modification of the BCR signal pathway are mechanisms that guide the B cell to its appropriate fate. For example, in the absence of coreceptor engagement, anti-sIgM antibodies induce apoptosis in the human Daudi B cell lymphoma cell line. ITIM-bearing B cell coreceptors that potentially may act as negative coreceptors include FcRgammaIIb, CD22, CD72, and CEACAM1 (CD66a). Although the role of CEACAM1 as an inhibitory coreceptor in T cells has been established, its role in B cells is poorly defined. We show that anti-sIgM antibody and PI3K inhibitor LY294002-induced apoptosis are reduced significantly in CEACAM1 knock-down clones compared with WT Daudi cells and that anti-sIgM treatment induced CEACAM1 tyrosine phosphorylation and association with SHP-1 in WT cells. In contrast, treatment of WT Daudi cells with anti-CD19 antibodies does not induce apoptosis and has reduced tyrosine phosphorylation and SHP-1 recruitment to CEACAM1. Thus, similar to its function in T cells, CEACAM1 may act as an inhibitory B cell coreceptor, most likely through recruitment of SHP-1 and inhibition of a PI3K-promoted activation pathway. Activation of B cells by anti-sIgM or anti-CD19 antibodies also leads to cell aggregation that is promoted by CEACAM1, also in a PI3K-dependent manner.
Lobo
Elizabeth O
EO
Division of Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA.
Zhang
Zhifang
Z
Shively
John E
JE
D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D018941:Antigens, CD19 / Q000187:drug effects / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D015703:Antigens, CD; D018941:Antigens, CD19; D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D011947:Receptors, Antigen, B-Cell; C069847:CD66 antigens; C509249:PTPN6 protein, human