Interference with Immunoglobulin (Ig)α Immunoreceptor Tyrosine–Based Activation Motif (Itam) Phosphorylation Modulates or Blocks B Cell Development, Depending on the Availability of an Igβ Cytoplasmic Tail

Abstract

To determine the function of immunoglobulin (Ig)α immunoreceptor tyrosine–based activation motif (ITAM) phosphorylation, we generated mice in which Igα ITAM tyrosines were replaced by phenylalanines (IgαFF/FF). IgαFF/FFmice had a specific reduction of B1 and marginal zone B cells, whereas B2 cell development appeared to be normal, except that λ1 light chain usage was increased. The mutants responded less efficiently to T cell–dependent antigens, whereas T cell–independent responses were unaffected. Upon B cell receptor ligation, the cells exhibited heightened calcium flux, weaker Lyn and Syk tyrosine phosphorylation, and phosphorylation of Igα non-ITAM tyrosines. Strikingly, when the Igα ITAM mutation was combined with a truncation of Igβ, B cell development was completely blocked at the pro-B cell stage, indicating a crucial role of ITAM phosphorylation in B cell development.

Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner

“…These studies also suggested a role for Ig␤ in trafficking the BCR complex to an MHC class II-rich late endosomal compartment (30). Mice with mutations in Ig␣ have alterations in BCR levels on developing B cells (31,32). B cells developing in mice in which the Ig␣ ITAM tyrosines were replaced with phenylalanines displayed increased BCR levels on most B cell subsets (32).…”

“…Mice with mutations in Ig␣ have alterations in BCR levels on developing B cells (31,32). B cells developing in mice in which the Ig␣ ITAM tyrosines were replaced with phenylalanines displayed increased BCR levels on most B cell subsets (32). In contrast, developing B cells expressing a BCR complex with two intracellular Ig␣ signaling chains have decreased BCR levels, increased constitutive BCR internalization, and an anergic phenotype (31).…”

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

“…The cytoplasmic tails of Igα and Igβ each contain an immunoreceptor tyrosine‐based activation motif (ITAM) with two conserved tyrosines that are crucial for the development and maintenance of mature B cells (Reth, 1989; Torres et al , 1996; Kraus et al , 2001, 2004; Reichlin et al , 2001). Upon antigen ligation and opening of the BCR, the spleen tyrosine kinase (Syk) phosphorylates and interacts with the ITAM tyrosines of Igα and Igβ (Rolli et al , 2002).…”

B Cell Progenitors Are Arrested in Maturation but Have Intact VDJ Recombination in the Absence of Ig-α and Ig-β

“…Mice bearing mutations in or deletions of the cytoplasmic portion of both Ig-␣ and Ig-␤ also show complete block at the pro-B cell stage of B cell development (17,18). However, the same mutations in either Ig-␣ or Ig-␤ cause a partial block at the pre-B cell stage and a more severe arrest at the immature B cell stage, demonstrating that Ig-␣ and Ig-␤ have redundant signaling functions, at least during pre-BCR signaling (17)(18)(19).…”