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.