Btk at the Pre-B Cell Receptor Checkpoint

Signalling from the BCR or its immature form, the pre-BCR, was shown to be crucial for B cell development. Gene-targeted mice have defined differential roles of components of the (pre-) BCR complex or its downstream signalling pathways. One of the proteins involved in (pre-) BCR signalling is the cytoplasmic protein Bruton’s tyrosine kinase (Btk). Mice deficient in Btk have B cell differentiation defects resulting in an X-linked immunodefi ciency (xid) phenotype. The xid phenotype is characterized by a reduction in the number of peripheral B cells and the residual B cell have an immature phenotype, indicating that the lack of Btk causes a block in peripheral B cell differentiation. Btk-deficient mice have low levels of serum IgM and IgG3, peritoneal B-1 cells are lacking and these mice are not able to respond normally to infection with T cell independent antigens. In contrast, humans with mutations in the Btk gene develop the much more severe X-linked agammaglobulinemia (XLA), which is characterized by an almost complete block at the pre-B cell stage in the BM, indicating a role for Btk at the pre-BCR checkpoint. Boys with XLA have almost no peripheral B cells and have very low serum levels of all Ig classes. Therefore, XLA patients hardly respond to bacterial antigens, but treatment with antibiotics and gamma globulin therapy is very effective. To determine the exact role of Btk during early B cell development in the mouse bone marrow, we studied pre-BCR checkpoint functions in the Btk-defi cient mice. Pre-BCR signalling regulates the clonal expansion of pre-B cells and subsequent downregulation of the V(D)J recombinase system ensures allelic exclusion. Furthermore, downregulation of surrogate light chain (SLC) and IL-7R expression terminates the proliferation of large pre-B cells and induces differentiation into small pre-B cells when the cells have stopped cycling. Modulating the expression of various cell surface and intracellular proteins regulates cellular maturation during the transition of large into small pre-B cells. In small pre-B cells, the rearrangement machinery is activated again and L chain recombination is initiated. Functional L chain rearrangement leads to the expression of the BCR on the cell surface and the cells are transferred to the IgM+ immature B cell compartment.

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