Formation of the pre-B-cell receptor and signaling through this receptor provide an important checkpoint that mediates the transition between the pro-B cell and the pre-B cell. In mice that either lack λ5 or have mutant heavy-chain genes that cannot produce the transmembrane domain, the pre-B-cell receptor cannot be formed and B-cell development is blocked after heavy-chain gene rearrangement. In normal B-cell development, the pre-B-cell receptor complex is expressed transiently, perhaps because the production of λ5 mRNA stops as soon as pre-B-cell receptors begin to be formed. Although present at only low levels on the cell surface, the pre-B-cell receptor generates signals required for the transition from pro-B cell to pre-B cell. No antigen or other external ligand seems to be involved in signaling by the receptor. Instead, pre-B-cell receptors are thought to interact with each other, forming dimers or oligomers that generate signals as described in Section 7-16. Dimerization involves ‘unique’ regions in the amino termini of λ5 and VpreB proteins that are not present in other immunoglobulin-like domains and which mediate the cross-linking of adjacent pre-B-cell receptors on the cell surface (Fig. 8.6). PreB-cell receptor signaling requires the scaffold protein BLNK and Bruton’s tyrosine kinase (Btk), an intracellular Tec-family tyrosine kinase (see Section 7-20). In humans and mice, deficiency of BLNK leads to a block in B-cell development at the pro-B-cell stage. In humans, mutations in the BTK gene cause a profound B-lineage-specific immune deficiency, Bruton’s X-linked agammaglobulinemia (XLA), in which no mature B cells are produced. The block in B-cell development caused by mutations in BTK is almost total, interrupting the transition from pre-B cell to immature B cell. A similar, but less severe, defect called X-linked immunodeficiency, or xid, arises from mutations in the Btk gene in mice.
8-4 Pre-B-cell receptor signaling inhibits further heavy-chain locus rearrangement and enforces allelic exclusion.
The signaling generated by pre-B-cell receptor clustering halts further rearrangement of the heavy-chain locus and allows the pro-B cell to become sensitive to IL-7. This induces cell proliferation, initiating the transition to the large
Fig. 8.6 The pre-B-cell receptor initiates signaling through spontaneous dimerization induced by the unique regions of VpreB and λ5. Two surrogate protein chains, VpreB (orange) and λ5 (green), substitute for a light chain and bind to a heavy chain, thus allowing its surface expression. VpreB substitutes for the light-chain V region in this surrogate interaction, while λ5 takes the part of the light-chain constant region. Both VpreB and λ5 contain ‘unique’ amino-terminal regions that are not present in other immunoglobulin-like domains, shown here as unstructured tails extending out from the globular domains. These amino-terminal regions associated with one pre-B-cell receptor can interact with the corresponding regions on the adjacent pre-B-cell receptor, promoting the spontaneous formation of pre-Bcell receptor dimers on the cell surface. Dimerization generates signaling from the pre-B-cell receptor that is dependent on the presence of the ITAM-containing signaling chains Igα and Igβ. The signals cause the inhibition of RAG-1 and RAG-2 expression and the proliferation of the large pre-B cell. Courtesy of Chris Garcia.