Powered by pairing: The surrogate light chain amplifies immunoglobulin heavy chain signaling and pre-selects the antibody repertoire

Vettermann, Christian; Herrmann, Kai; Jäck, Hans‐Martin

doi:10.1016/j.smim.2006.01.001

Cited by 44 publications

(47 citation statements)

References 168 publications

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“…Once a functional V H exon has been generated, a heavy (H) chain is produced, which assembles with the surrogate light (L) chain and the signal molecules Igα/Igβ to form the pre-B cell receptor complex (pre-BCR). The pre-BCR provides signals for clonal expansion, survival, and differentiation into pre-B cells (2). Of the two IgH alleles, only one contributes to the BCR-a phenomenon known as allelic exclusion.…”

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confidence: 99%

Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

Lutz

Heideman

Roth

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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B-lymphocyte development is dictated by the protein products of functionally rearranged Ig heavy (H) and light (L) chain genes. Ig rearrangement begins in pro-B cells at the IgH locus. If pro-B cells generate a productive allele, they assemble a pre-B cell receptor complex, which signals their differentiation into pre-B cells and their clonal expansion. Pre-B cell receptor signals are also thought to contribute to allelic exclusion by preventing further IgH rearrangements. Here we show in two independent mouse models that the accumulation of a stabilized μH mRNA that does not encode μH chain protein specifically impairs pro-B cell differentiation and reduces the frequency of rearranged IgH genes in a dose-dependent manner. Because noncoding IgH mRNA is usually rapidly degraded by the nonsense-mediated mRNA decay machinery, we propose that the difference in mRNA stability allows pro-B cells to distinguish between productive and nonproductive Ig gene rearrangements and that μH mRNA may thus contribute to efficient H chain allelic exclusion.

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confidence: 99%

Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

Lutz

Heideman

Roth

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…During this process, imperfect heavy chains (HCs), nonfunctional V H -V L pairings, and cells that express antibodies to self antigens must be eliminated at the pre-B cell stage of development. Over the last 20 years, the mechanism by which this is accomplished has largely been elucidated (10). The central feature of this mechanism involves the assembly of a pre-B cell receptor (pre-BCR) at the pro-B-pre-B cell junction of the developmental B cell cascade (10).…”

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confidence: 99%

“…Over the last 20 years, the mechanism by which this is accomplished has largely been elucidated (10). The central feature of this mechanism involves the assembly of a pre-B cell receptor (pre-BCR) at the pro-B-pre-B cell junction of the developmental B cell cascade (10). The pre-BCR has a structure different from that of mature Ig.…”

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confidence: 99%

“…Over the years, there has been much discussion and experimentation surrounding several aspects of the relationship between B cell and pre-BCRs (10,11,14,16). These discussions have centered on the structural relationships between the molecules, the role of the peptide extensions on the (SLC components, and whether antigen binding by the pre-BCR was important to its function as a ''quality control'' element in B cell development.…”

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Combinatorial surrobody libraries

Yee

Chan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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A unique type of combinatorial protein libraries has been constructed. These libraries are based on the pre-B cell receptor (pre-BCR). The pre-BCR is a protein that is produced during normal development of the antibody repertoire. Unlike that of canonical antibodies, the pre-BCR subunit is a trimer that is composed of an antibody heavy chain paired with two surrogate light chain (SLC) components. Combinatorial libraries based on these pre-BCR proteins in which diverse heavy chains are paired with a fixed SLC were expressed in mammalian, Escherichia coli, and phagemid systems. These libraries contain members that have nanomolar affinity for antigen. We term this type of antigen-binding protein a ''surrobody'' to distinguish it from the canonical antibody molecule.antibody engineering ͉ combinatorial antibody libraries ͉ surrogate light chain

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“…These receptors thereby serve as a quality control mechanism to establish whether the V(D)J rearrangement process, necessary to assemble Ig genes from component gene segments, created a functional Ig gene. For example, before L chain rearrangement, progression from the progenitor (pro) to precursor (pre) stage of development depends on the ability of the H chain to form a so called precursor B cell receptor (preBCR) 4 complex with the surrogate L chain (SLC) components 5 and VpreB and signal transducers Ig␣ and Ig␤ (2)(3)(4). B cells that synthesize no H chains or H chains that fail to form signalingcompetent receptor complexes (either with or without the SLC) due to intrinsic structural flaws are eliminated because of the absence of a preBCR signal.…”

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Multiple Levels of Selection Responsive to Immunoglobulin Light Chain and Heavy Chain Structures Impede the Development of Dμ-Expressing B Cells

Güloğlu

Smith

Roman

2008

The Journal of Immunology

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The truncated/VH-less mouse H chain Dμ forms precursor B cell receptors with the surrogate L chain complex that promotes allelic exclusion but not other aspects of pre-B cell development, causing most progenitor B cells expressing this H chain to be eliminated at the pre-B cell checkpoint. However, there is evidence that Dμ-λ1 complexes can be made and are positively selected during fetal life but cannot sustain adult B lymphopoiesis. How surrogate and conventional L chains interpret Dμ’s unusual structure and how that affects signaling outcome are unclear. Using nonlymphoid and primary mouse B cells, we show that secretion-competent λ1 L chains could associate with both full-length H chains and Dμ, whereas secretion-incompetent λ1 L chains could only do so with full-length H chains. In contrast, Dμ could not form receptors with a panel of κ L chains irrespective of their secretion properties. This was due to an incompatibility of Dμ with the κ-joining and constant regions. Finally, the Dμ-λ1 receptor was less active than the full-length mouse μ-λ1 receptor in promoting growth under conditions of limiting IL-7. Thus, multiple receptor-dependent mechanisms operating at all stages of B cell development limit the contribution of B cells with Dμ H chain alleles to the repertoire.

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Powered by pairing: The surrogate light chain amplifies immunoglobulin heavy chain signaling and pre-selects the antibody repertoire

Cited by 44 publications

References 168 publications

Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

Pro-B cells sense productive immunoglobulin heavy chain rearrangement irrespective of polypeptide production

Combinatorial surrobody libraries

Multiple Levels of Selection Responsive to Immunoglobulin Light Chain and Heavy Chain Structures Impede the Development of Dμ-Expressing B Cells

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