Igβ tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization

Immunoglobulin (Ig)alpha and Ig beta initiate B cell receptor (BCR) signaling through immune receptor tyrosine activation motifs (ITAMs) that are targets of SH2 domain-containing kinases. To examine the function of Ig beta. ITAM tyrosine resides in mature B cells in vivo, we exchanged these residues for alanine by gene targeting (Ig beta AA). Mutant mice showed normal development of all B cell subtypes with the exception of B1 cells that were reduced by fivefold. However, primary B cells purified from Ig beta AA mice showed significantly decreased steady-state and ligand-mediated BCR internalization and higher levels of cell surface IgM and IgD. BCR cross-linking resulted in decreased Src and Syk activation but paradoxically enhanced and prolonged BCR signaling, as measured by cellular tyrosine phosphorylation, Ca++ flux, AKT, and ERK activation. In addition, B cells with the ITAM mutant receptor showed an enhanced response to a T-independent antigen. Thus, Ig beta ITAM tyrosines help set BCR signaling threshold by regulating receptor internalization.