Intrinsic bias and public rearrangements in the human immunoglobulin Vλ light chain repertoire

Hoi, Kam Hon; Ippolito, Gregory C.

doi:10.1038/gene.2013.10

Cited by 36 publications

(28 citation statements)

References 37 publications

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“…eOD-GT8 was bound by B cells expressing VH1-2 and this public LC in 11 of 18 donors and in multiple instances within 6 donors (Figure 3E). Whereas public LCs have been described in repertoire studies (19, 29, 30) (31), these data demonstrated epitope-specific public LC usage in humans. The length of the VH1-2 H-CDR3s correlated strongly with the eOD-GT8 affinity for Vκ3-20 + Jκ1-01 + public LC Abs (Figure 3F).…”

Section: Resultsmentioning

confidence: 73%

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

et al. 2018

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One Sentence Summary: Inspection of the naive B cell repertoire specific for an HIV vaccine immunogen provides actionable information for human vaccine design and advancement. Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful, so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre-Phase I ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the Env CD4 binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non-VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA-class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities (KD) to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine-elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement.

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Section: Resultsmentioning

confidence: 73%

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

et al. 2018

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“…The same biases have been observed among transcripts generated from transgenic mice that carry a human heavy chain mini-locus (62), while in NOD-scid-IL2Rγ null mice that had been reconstituted with human hematopoietic stem cells, typical patterns of biased usage were seen amongst the expressed light chain genes (63). Recent studies in monozygotic twins show that they share utilization frequencies for both the heavy and light chain genes (46, 63), with correlations in a similar range to replicate biological samples. When one twin was investigated following lymphocyte ablation therapy, the reconstituted repertoire showed the same utilization patterns (46).…”

Section: Biases In Combinatorial Diversity and The Shaping Of The Repmentioning

confidence: 71%

The Shape of the Lymphocyte Receptor Repertoire: Lessons from the B Cell Receptor

Jackson¹,

Kidd²,

Wang³

et al. 2013

Front. Immunol.

105

112

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Both the B cell receptor (BCR) and the T cell receptor (TCR) repertoires are generated through essentially identical processes of V(D)J recombination, exonuclease trimming of germline genes, and the random addition of non-template encoded nucleotides. The naïve TCR repertoire is constrained by thymic selection, and TCR repertoire studies have therefore focused strongly on the diversity of MHC-binding complementarity determining region (CDR) CDR3. The process of somatic point mutations has given B cell studies a major focus on variable (IGHV, IGLV, and IGKV) genes. This in turn has influenced how both the naïve and memory BCR repertoires have been studied. Diversity (D) genes are also more easily identified in BCR VDJ rearrangements than in TCR VDJ rearrangements, and this has allowed the processes and elements that contribute to the incredible diversity of the immunoglobulin heavy chain CDR3 to be analyzed in detail. This diversity can be contrasted with that of the light chain where a small number of polypeptide sequences dominate the repertoire. Biases in the use of different germline genes, in gene processing, and in the addition of non-template encoded nucleotides appear to be intrinsic to the recombination process, imparting “shape” to the repertoire of rearranged genes as a result of differences spanning many orders of magnitude in the probabilities that different BCRs will be generated. This may function to increase the precursor frequency of naïve B cells with important specificities, and the likely emergence of such B cell lineages upon antigen exposure is discussed with reference to public and private T cell clonotypes.

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“…Convergent (or public) CDR3s in unrelated individuals are common in the IGK and IGL light chain repertoires, due to the limited number of gene segments and the single junction encoding them (18,19). Low-frequency convergent IGH sequences have also been reported in patients with viral infections or recent vaccination, including responses to repetitive polysaccharide vaccine antigens (7,8,13,20).…”

Section: Discussionmentioning

confidence: 99%

B-cell repertoire responses to varicella-zoster vaccination in human identical twins

Wang¹,

Liu²,

Cavanagh

et al. 2014

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

101

105

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Adaptive immune responses in humans rely on somatic genetic rearrangements of Ig and T-cell receptor loci to generate diverse antigen receptors. It is unclear to what extent an individual's genetic background affects the characteristics of the antibody repertoire used in responding to vaccination or infection. We studied the B-cell repertoires and clonal expansions in response to attenuated varicellazoster vaccination in four pairs of adult identical twins and found that the global antibody repertoires of twin pair members showed high similarity in antibody heavy chain V, D, and J gene segment use, and in the length and features of the complementarity-determining region 3, a major determinant of antigen binding. These twin similarities were most pronounced in the IgM-expressing B-cell pools, but were seen to a lesser extent in IgG-expressing B cells. In addition, the degree of antibody somatic mutation accumulated in the B-cell repertoire was highly correlated within twin pair members. Twin pair members had greater numbers of shared convergent antibody sequences, including mutated sequences, suggesting similarity among memory B-cell clonal lineages. Despite these similarities in the memory repertoire, the B-cell clones used in acute responses to ZOSTAVAX vaccination were largely unique to each individual. Taken together, these results suggest that the overall Bcell repertoire is significantly shaped by the underlying germ-line genome, but that stochastic or individual-specific effects dominate the selection of clones in response to an acute antigenic stimulus.H uman responses to infectious diseases or vaccinations rely on many different cell populations, soluble mediators, and interactions between cells. Prior studies of identical twins have highlighted aspects of human immunity that are heavily influenced by the germ-line genome, such as the proportions of particular leukocyte subsets (1). In addition to the germ line-encoded genes that affect the responses of immune cells, mammalian immune systems also make use of somatic genetic rearrangements to produce diverse repertoires of immunoglobulins (Igs) and T-cell receptors (TCRs) for specific recognition of foreign antigens. Antibody and TCR sequences are generated through the combinatorial use of a set of predetermined gene segments in the genome, as well as by more random exonuclease digestion of the ends of the gene segments, and addition of nontemplated bases at the junctions between gene segments. Clonal expansion of the populations of cells that recognize particular pathogens provides immune system memory of prior exposures.The germ-line genome sequence plays a role in the initial generation and selection of antibody and T-cell receptor repertoires in each individual, as demonstrated in prior work (2-6). Whether such genetic effects have a prominent effect on the clonal B-cell responses to particular pathogens or vaccinations is much less clear. In adult humans, it is possible that the accumulation of the effects of responses to prior antigenic exposures in...

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Intrinsic bias and public rearrangements in the human immunoglobulin Vλ light chain repertoire

Cited by 36 publications

References 37 publications

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

The Shape of the Lymphocyte Receptor Repertoire: Lessons from the B Cell Receptor

B-cell repertoire responses to varicella-zoster vaccination in human identical twins

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