TCRβ Allelic Exclusion in Dynamical Models of V(D)J Recombination Based on Allele Independence

Farcot, Etienne; Bonnet, Marie-Laure; Jaeger, Sébastien; Spicuglia, Salvatore; Fernandez, Bastien; Ferrier, Pierre

doi:10.4049/jimmunol.0904182

Cited by 8 publications

(7 citation statements)

References 64 publications

(126 reference statements)

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“…Previous studies have shown that chromatin remodelling and transcription of the Ig and TCR loci is important for successful recombination and allelic exclusion of the unused gene rearrangement262728. Epigenetic modification may also be an important factor in determining the order of rearrangement for the two chromosomes, as unequal methylation levels at the onset of recombination could delay the rearrangement of the methylated chromosome29. In this paper, we observed an increase in variance when comparing chromosomal usage ratios in productive versus non-productive sequences, consistent with a model where one chromosome is preferentially rearranged 1.5-fold more often (on average).…”

Section: Discussionmentioning

confidence: 99%

Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells

et al. 2016

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The adaptive immune system's capability to protect the body requires a highly diverse lymphocyte antigen receptor repertoire. However, the influence of individual genetic and epigenetic differences on these repertoires is not typically measured. By leveraging the unique characteristics of B, CD4+ T and CD8+ T-lymphocyte subsets from monozygotic twins, we quantify the impact of heritable factors on both the V(D)J recombination process and on thymic selection. We show that the resulting biases in both V(D)J usage and N/P addition lengths, which are found in naïve and antigen experienced cells, contribute to significant variation in the CDR3 region. Moreover, we show that the relative usage of V and J gene segments is chromosomally biased, with ∼1.5 times as many rearrangements originating from a single chromosome. These data refine our understanding of the heritable mechanisms affecting the repertoire, and show that biases are evident on a chromosome-wide level.

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Section: Discussionmentioning

confidence: 99%

Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells

et al. 2016

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“…It is increasingly recognized that cell fate decisions and underlying genetic circuits are subjected to such stochastic fluctuations to generate non‐genetic cellular diversity; with, in mammals, intrinsic noise in gene expression mainly depending on epigenetic‐regulated chromatin changes . When integrated at the level of a whole cell‐population, this model makes it possible to readily predict the distinct TCRβ cell genotypes and allelic exclusion/inclusion profiles from wild‐type and mutant mice . In keeping with the same concepts, we anticipate that corresponding features at other gene loci could likewise be interpreted.…”

Section: The Control Of Allelic Exclusion: Deterministic Stochastic mentioning

confidence: 77%

“…On the other hand, highly stochastic scenarios are hard to reconcile with the relatively high proportion (40–45%) of cells displaying fully rearranged, productive and non‐productive, IgH or TCRβ alleles. Using TCRβ allelic exclusion as a reference system, we proposed that a dynamic combination of the two concepts, determinism and stochasticity – as modelled using the Markov chain formalism, better accounts for the distribution of TCRβ genotypes emerging from early T‐cell development; (Fig. b,c).…”

Section: The Control Of Allelic Exclusion: Deterministic Stochastic mentioning

confidence: 99%

Epigenetic aspects of lymphocyte antigen receptor gene rearrangement or ‘when stochasticity completes randomness’

2013

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SummaryTo perform their specific functional role, B and T lymphocytes, cells of the adaptive immune system of jawed vertebrates, need to express one (and, preferably, only one) form of antigen receptor, i.e. the immunoglobulin or T-cell receptor (TCR), respectively. This end goal depends initially on a series of DNA cis-rearrangement events between randomly chosen units from separate clusters of V, D (at some immunoglobulin and TCR loci) and J gene segments, a biomolecular process collectively referred to as V(D)J recombination. V(D)J recombination takes place in immature T and B cells and relies on the so-called RAG nuclease, a site-specific DNA cleavage apparatus that corresponds to the lymphoid-specific moiety of the VDJ recombinase. At the genome level, this recombinase's mission presents substantial biochemical challenges. These relate to the huge distance between (some of) the gene segments that it eventually rearranges and the need to achieve cell-lineage-restricted and developmentally ordered routines with at times, mono-allelic versus bi-allelic discrimination. The entire process must be completed without any recombination errors, instigators of chromosome instability, translocation and, potentially, tumorigenesis. As expected, such a precisely choreographed and yet potentially risky process demands sophisticated controls; epigenetics demonstrates what is possible when calling upon its many facets. In this vignette, we will recall the evidence that almost from the start appeared to link the two topics, V(D)J recombination and epigenetics, before reviewing the latest advances in our knowledge of this joint venture.

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“…However, interallelic crosstalk cannot fully explain H chain exclusion in the shark since linked IgH and their alleles rearrange independently of each other. Perhaps more relevant to the shark observations is a model recently generated for the TCRβ locus, which proposes that if the two alleles are autonomous and activated stochastically they are unlikely to initiate recombination at the same time [10]. A sufficient time lag between the two steps, D to J and V to DJ, would permit a productive VDJ at the first allele to effect inhibition on the second, rearranging allele.…”

Section: Discussionmentioning

confidence: 99%

“…Both alleles are poised for rearrangement, but it is the asynchrony at the VH to DJ step that initiates allelic exclusion and events leading to a single type of antigen receptor expressed per lymphocyte. The underlying causes for one gene acting ahead of the other are the subject of some controversy [8–10]. …”

Section: Introductionmentioning

confidence: 99%

The Multiple Shark Ig H Chain Genes Rearrange and Hypermutate Autonomously

Zhu

Feng

Weedon

et al. 2011

The Journal of Immunology

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Sharks and skates are representatives of the earliest vertebrates with an immune system based on V(D)J rearrangement. They possess a unique Ig gene organization consisting of 15 to >50 individual IgM loci, each with one VH, two DH, one JH and one set of constant region exons. The present study attempts to understand how multiple Ig genes are regulated with respect to rearrangement initiation and to targeting during somatic hypermutation. The linkage of three single-copy IgH genes was determined, and single-cell genomic PCR studies in a neonatal animal was used to examine any relationship between relative gene position and likelihood of rearrangement. Our results show that 1–3 IgH genes are activated independently of linkage or allelic position and the data best fit with a probability model based on the hypothesis that V(D)J rearrangement occurs as a sequence of trials within the B cell. In the neonatal cell set two closely related IgH, G2A and G2B, rearranged at similar frequencies and their membrane forms were expressed at similar levels, like in other young animals. However, older animals displayed a bias in favor of the G2A isotype, which suggests that although rearrangement at G2A and G2B was randomly initiated during primary repertoire generation, the two very similar IgM sequences appear to be differentially expressed with age and exposure to antigen. We performed genomic single-cell PCR on B cells from an immunized individual to study AID targeting and found that hypermutation, like V(D)J rearrangement, occurred independently among the many shark IgH.

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TCRβ Allelic Exclusion in Dynamical Models of V(D)J Recombination Based on Allele Independence

Abstract: Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/06/28/jimmunol.090418

Cited by 8 publications

References 64 publications

Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells

Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells

Epigenetic aspects of lymphocyte antigen receptor gene rearrangement or ‘when stochasticity completes randomness’

The Multiple Shark Ig H Chain Genes Rearrange and Hypermutate Autonomously

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