B cell development and activation defects resulting in xid-like immunodeficiency in BLNK/SLP-65-deficient mice

Abstract

Engagement of the B cell receptor (BCR) leads to the activation of tyrosine kinases and other signaling molecules that ultimately determine the type and magnitude of the B lymphocyte's cellular response. The adaptor protein BLNK/SLP-65 plays a pivotal role in BCR signal transduction by coupling Syk activation to downstream elements such as Grb2, phospholipase C-gamma, Vav and Nck. We have generated BLNK(-/-) mice to determine the physiological role of this protein in B cell development and activation. BLNK(-/-) mice exhibit an incomplete block in B cell development with a severe inhibition of pro-B to pre-B cell differentiation. BLNK(-/-) sIgM(+) cells can develop, seed the peripheral lymphoid tissues and accumulate in numbers overtime. However, these mutant B cells failed to mature and are non-responsive to BCR cross-linking in terms of proliferation and up-regulation of activation markers such as CD69 and CD86 (B7-2). In addition, the CD5(+) subset of B cells is absent. The immune response to T cell-independent antigen but not T cell-dependent antigen is also impaired. Overall, the phenotype of BLNK(-/-) mice bears a striking resemblance to that of xid mice which is the murine model of human XLA that has a mutation in Bruton's tyrosine kinase. This raises the interesting possibility that mutation in BLNK/SLP-65 may be responsible for certain human immunodeficiencies.

Transitional Type 1 and 2 B Lymphocyte Subsets Are Differentially Responsive to Antigen Receptor Signaling

“…In separate studies, we have shown that at least two components of the BCR signalosome, BTK and PLC-␥2, are required for the activation of NF-B and transcriptional up-regulation of the bcl-x gene (58), 2 further supporting an involvement of the BCR signaling in T2 B cell responses. Like BTK and PLC-␥2, other components of the BCR signalosome including phosphatidylinositol 3-kinase, Vav, and B cell linker protein are involved in the transition of immature B cells to more mature stages (27,28,40,(42)(43)(44)(45). The opposite biological responses of T1 versus T2 and an involvement of the BCR signaling components in this process is also supported by a recent study published during the preparation of this manuscript (65).…”

Transitional B Cell Fate Is Associated with Developmental Stage-Specific Regulation of Diacylglycerol and Calcium Signaling upon B Cell Receptor Engagement

“…We and others have previously demonstrated that BTK deficiency leads to a severe mature FoB cell deficiency, despite intact T2 and mature MZ B cell subsets, termed Xid (xid) in mice (19 -22). An xid-like phenotype is also observed in animals with gene-targeted deletion of PLC-␥2, which is a direct target of BTK, and B cell linker protein (BLNK), an adaptor which facilitates BTK and PLC-␥2 interaction (23)(24)(25)(26)(27). These observations support an active role for BCR signaling, particularly the BTK/PLC-␥2 signaling axis, in the differentiation of T2 into mature FoB cells (3,4,15,25,26,28).…”

Receptor-Facilitated Antigen Presentation Requires the Recruitment of B Cell Linker Protein to Igα

“…To determine the mechanisms underlying these complex functions will require identification of the specific molecules and domains responsible for receptor trafficking. As deletion of BLNK impairs B cell development (53)(54)(55), studies in deficient mice are likely to be unrevealing.…”