Ia binding ligands and cAMP stimulate nuclear translocation of PKC in B lymphocytes

Abstract

Altered subcellular distribution and activity of protein kinase C (PKC) is associated with transmembrane signalling in a variety of systems in which receptor occupancy leads to increased hydrolysis of polyphosphoinositides. Here we report evidence that in B lymphocytes, cyclic-cAMP-generating signal transduction pathways can activate translocation of PKC from the cytosol to the nucleus. Elevated cAMP levels and translocation of PKC to the nucleus are induced by antibodies against Ia antigens in normal B lymphocytes. Further, cAMP analogues mediate the translocation of PKC to the nucleus of these cells. These findings suggest that in physiological situations, ligation of B-lymphocyte Ia molecules by helper T cells leads to increased cAMP production which in turn causes PKC translocation to the nucleus. In view of recent observations that antibodies against Ia antigens induce differentiation of B cells, we conclude that nuclear PKC may function in the regulation of gene expression.

The staphylococcal toxic shock syndrome toxin 1 triggers B cell proliferation and differentiation via major histocompatibility complex-unrestricted cognate T/B cell interaction.

“…mAbs to MHC class II antigens modulate the proliferation and Ig production of B cells triggered with a variety of mitogens (28,29). Engagement of MHC class II molecules by mAbs is associated with the accumulation of the second messenger cAMP and the translocation of protein kinase C from the cytosol to the nuclei oftreated B cells (30). Evidence presented elsewhere (Mourad, W, T. Chatila, and R. S. Geha, manuscript submitted for publication) demonstrates that TSSTI synergizes with antibodies to surface IgM to induce vigorous B cell proliferation.…”

“…The resultant B cells were further depleted of residual T cells and monocytes by treatment with OKT3 and OKMI, respectively, followed by rabbit complement (Pel-Freeze Biologicals, Rogers, AR) . High density B cells were then obtained by centrifugation over a discontinuous percoll gradient (30,45,50,60, and 90%) and by collecting the cells at the interface between 50-60% layers. The resulting B cell populations contained >98% CD20' cells and no detectable CD3' or CDIlb/CD18' cells .…”

Ligation of HLA-DR Molecules on B Cells Induces Enhanced Expression of IgM Heavy Chain Genes in Association with Syk Activation

“…Mouse IgG and mouse IgG2a were purchased from BioPur AG (Bubendorf, Switzerland) and Biogenesis (Poole, United Kingdom), respectively. F(abЈ) 2 fragments of L243 and mouse IgG were prepared, using ImmunoPure F(abЈ) 2 preparation kits (Pierce) with extensive dialysis to remove residual Fc fragments. L243, control mouse IgG, F(abЈ) 2 of L243, and F(abЈ) 2 of mouse IgG were conjugated with biotin (ImmunoPure NHS-LC-Biotin, Pierce).…”

“…Thus, signals transmitted to monocytes via HLA molecules are involved in determining immune response patterns. It is highly conceivable that signals transmitted by class II MHC molecules in B cells, in regulating antigen-presenting cell function during cognate T-B cell interactions, are important, for the following reasons: (a) cross-linking class II molecules induces an increase in intracellular calcium and cAMP in mouse or human B cell lines (2)(3)(4)(5); (b) class II MHC-mediated signals lead to homotypic aggregation of B cells (6); (c) cross-linking of HLA-DR molecules on B cells induces apoptosis (7); (d) class II MHC molecules without the intracellular domain expressed on B lymphoma cells will not lead to an increase in cAMP and subsequent CD80 up-regulation, when stimulated with a CD28-expressing autoreactive T hybridoma cells (8); (e) cytoplasmic domain mutants of class II MHC abrogate generation of intracelluar cAMP (9) and translocation of PKC (10); and (f) cross-linking of HLA-DR molecules expressed on B cells induces phosphorylation of Src family kinases (Lyn, Fgr) (11) and Syk (12). Although functional consequences of such DR-mediated signaling events induced by T cells are largely unknown, these observations do raise the possibility that signaling through class II MHC molecules may affect B cell responses, including Ig secretion, upon TCR-TCR ligand interaction.…”

Signaling Through MHC Class II Molecules Blocks CD95-Induced Apoptosis

“…Early events stimulated by MHC class II include the activation of protein tyrosine kinases, protein kinase C, phosphatidylinositol 3-kinase, and elevated intracellular calcium (28,29). Ligation of MHC class II on murine B cells also activates adenylate cyclase and the production of cAMP (30,31).…”