Developmental Regulation of B Lymphocyte Immune Tolerance Compartmentalizes Clonal Selection from Receptor Selection

AbstractB lymphocyte development is a highly ordered process that involves immunoglobulin gene rearrangements, antigen receptor expression, and a learning process that minimizes the development of cells with reactivity to self tissue. Two distinct mechanisms for immune tolerance have been defined that operate during early bone marrow stages of B cell development: apoptosis, which eliminates clones of cells, and receptor editing, which spares the cells but genetically reprograms their autoreactive antigen receptors through nested immunoglobulin L chain gene rearrangements. We show here that sensitivity to antigen-induced apoptosis arises relatively late in B cell development and is preceded by a functionally distinct developmental stage capable of receptor editing. This regulation compartmentalizes clonal selection from receptor selection

FcγRIIB1 Inhibition of BCR-Mediated Phosphoinositide Hydrolysis and Ca2+ Mobilization Is Integrated by CD19 Dephosphorylation

AbstractThe B cell receptor for immunoglobulin G, FcγRIIB1, is a potent transducer of signals that block antigen-induced B cell activation. Coligation of FcγRIIB1 with B lymphocyte antigen receptors (BCR) causes premature termination of phosphoinositide hydrolysis and Ca2+ mobilization and inhibits proliferation. This inhibitory signal is mediated in part by phosphorylation of FcγRIIB1 and recruitment of phosphatases; however, the molecular target(s) of effectors is unknown. Here we report that FcγRIIB1 inhibition of BCR signaling is mediated in part by selective dephosphorylation of CD19, a BCR accessory molecule and coreceptor. CD19 dephosphorylation leads to failed CD19 association with phosphatidylinositol 3-kinase, and this in turn leads to termination of inositol-1,4,5-trisphosphate production, intracellular Ca2+ release, and Ca2+ influx. The results define a molecular circuit by which FcγRIIB signals block phosphoinositide hydrolysis