Protein tyrosine kinases couple the surface immunoglobulin of germinal center B cells to phosphatidylinositol-dependent and -independent pathways of rescue from apoptosis.
Considerable progress has been made recently in elucidating the intracellular signal transduction pathways which couple surface immunoglobulin (sIg) of resting B lymphocytes (BH) to the proliferative cycle. By contrast, nothing is known of the signals which couple the sIg of germinal center (GC) B cells not to mitogenesis but, instead, to the suppression of apoptosis: the present study examines the signaling pathways through which this response is achieved. GC B cells treated with anti-Ig exhibited enhanced phosphorylation on tyrosine for a number substrates: this was accompanied by a transient increase in inositol 1,4,5-trisphosphate, an increase in [Ca2+]i, and translocation of PKC from the cytosol. These changes could be provoked with Abs specific for IgG or IgA, the major sIg on GC B cells. Herbimycin A, an inhibitor of protein tyrosine kinases (PTK), uncoupled sIg on GC B cells from both the increase in [Ca2+]i and the rescue from apoptosis: the latter was only partially blocked by inhibitors of PKC and chelators of intracellular and extracellular Ca2+. These data indicate that not only do PTK link the antigen receptor (AgR) of GC B cells to both phosphatidylinositol (PI)-dependent and -independent routes of survival but also that tyrosine phosphorylation is critical for sIg-mediated rescue of this population from apoptosis. Moreover, despite the distinct functional responses observed following ligation of the AgR of resting BH lymphocytes and GC B cells, anti-Ig initiates a very similar pattern of second messenger change in these populations suggesting that bifurcation must occur at a more distal stage of the signaling process.
Knox
K A
KA
Department of Immunology, University of Birmingham, Medical School, Edgbaston, United Kingdom.
Gordon
J
J
D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000502:physiology*; D016227:Benzoquinones; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D003432:Cross-Linking Reagents; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D047029:Lactams, Macrocyclic; D014066:Palatine Tonsil / Q000166:cytology; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction
D016227:Benzoquinones; D002614:Chelating Agents; D003432:Cross-Linking Reagents; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D047029:Lactams, Macrocyclic; D010716:Phosphatidylinositols; D011809:Quinones; D011947:Receptors, Antigen, B-Cell; D017828:Rifabutin; C020754:herbimycin; D015544:Inositol 1,4,5-Trisphosphate; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D002118:Calcium