Integration of activatory and inhibitory signals in human B-cells

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21 Citations (Scopus)


Fcγ receptors type IIb1 (FcγRIIb1) inhibit B-cell activation when co-ligated with B-cell antigen receptors (BCR) by immune complexes. In murine B-cells the inhibition is mediated by the interaction of the phosphorylated immunoreceptor tyrosine-based inhibitory motif (P-ITIM) of FcγRIIb1 with the SH2 domain containing protein tyrosine phosphatase, SHP1. To clarify the mechanism of FcγRIIb mediated inhibition of human B-cells we have studied the association of signaling molecules with human FcγRIIb1 after co-ligating with BCR. FcγRIIb1 were affinity purified from the Burkitt lymphoma cell line, BL41. Several tyrosine phosphorylated proteins were co-isolated with FcγRIIb1 at 145, 110, and 50-60 kDa, which were not present in FcγRIIb1 free immune complexes. Among these molecules we have identified the p52 Shc adaptor protein. Furthermore, we have shown that the insolubilised synthetic peptide corresponding P-ITIM bound Shc, Lyn and the p75 and p110 unidentified tyrosine phosphorylated proteins. Here we describe that the cell membrane associated Shc is partially dephosphorylated in BCR-FcγRIIb1 co-ligated samples, suggesting that its function in regulating p21 ras monomeric G protein is impaired. Indeed, we have detected a lower p21 ras activity in BCR-FcγRIIb1 co-crosslinked samples. These data indicate that co-ligation of BCR and FcγRIIb1 interrupts signal transduction between protein tyrosine kinase activation and p21 ras mediated activation pathway. Since in contrast to the mouse B-cells both FcγRIIb1 and FcγRIIb2 are expressed in human B-cells, we have investigated the inhibitory function of the two receptors in FcγRIIb negative Burkitt lymphoma cell line ST486 transfected with FcγRIIb1 and FcγRIIb2, respectively. Both FcγRIIb1 and FcγRIIb2 inhibited the rise of intracellular Ca2+ induced by the crosslinking of BCR. The rate of the inhibition depended on the ratio of the co-crosslinked receptors (BCR-FcγRIIb1) to the crosslinked BCR (BCR-BCR). Co-crosslinking of the two receptors inhibited not only the capacitive Ca2+ entry but rather the total Ca2+ response in both FcγRIIb1 and FcγRIIb2 transfected human B-cells. CD19 represents the signal transduction unit of complement receptor, CR2 (CD21), and is responsible for the complement activating IgM-immune complex induced enhancement of B-cell activation. Co-crosslinking of CD19 and BCR was shown to enhance B-cell activation due to the recruitment of further signaling molecules to the activator complex by the phosphorylated tyrosine residues of CD19. Here we show a novel finding that co-ligation of CD19 with FcγRIIb1 inhibits the CD19-induced upregulation of Ca2+ response. The results indicate that IgG plus complement containing immune complexes may inhibit B-cell activation in vivo, due to the FcγRIIb1-mediated interruption of signal transduction via both BCR and CD19.

Original languageEnglish
Pages (from-to)93-100
Number of pages8
JournalImmunology letters
Issue number2-3
Publication statusPublished - Dec 2 1996


  • FcγRIIb
  • human B-cells
  • regulation
  • signal transduction

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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