Contribution of <i>TCR</i>-β Locus and HLA to the Shape of the Mature Human Vβ Repertoire

Melenhorst, J. Joseph; Lay, Matthew D. H.; Price, David A.; Adams, Sharon; Zeilah, Josette; Sosa, Edgardo; Hensel, Nancy F.; Follmann, Dean; Douek, Daniel C.; Davenport, Miles P.; Barrett, A. John

doi:10.4049/jimmunol.180.10.6484

Cited by 14 publications

(17 citation statements)

References 40 publications

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“…Notably, the relative frequency of gene segment usage established during recombination is very similar to that found after thymic selection [46]. Moreover, biased V β usage by human CD4 + and CD8 + T cells in neonatal and adult donors is highly correlated between unrelated individuals, and the correlation in biased V β expression patterns between CD4 + and CD8 + T cells can be dominantly determined by germline TCR β locus factors rather than thymic selection [48]. Other observed recombinatorial biases include the extent of the removal of nucleotides from the germline gene segments and additions of specific 'random' nucleotides.…”

Section: Recombinatorial Biasesmentioning

confidence: 62%

“…All these evidence strongly suggests that β-selection and TCRαβ heterodimer formation do not favor any particular V β -J β combinations. In addition, biased V β usage by human CD4 + and CD8 + T cells in neonatal and adult donors is highly correlated between unrelated individuals, and the correlation in biased V β expression patterns between CD4 + and CD8 + T cells can be explained by germline TCR β locus factors, but not TCR β allelic or HLA effects [63].…”

Section: The Role Of Thymic Selection In Tcr Sharingmentioning

confidence: 99%

“…V(D)J recombination has been shown to be regulated at multiple levels. Apart from cis-elements in the immune receptor loci, including recombination signal sequence, enhancers and promoters [48,65], some trans-elements have been shown to play an important part in the regulation of V(D)J recombination [66][67][68]. Moreover, accumulating evidence has demonstrated the role of epigenetic factors in the regulation of V(D)J recombination, probably by altering the chromatin accessibility at the immune receptor loci [66,[69][70][71][72][73][74][75].…”

Section: Future Challengesmentioning

confidence: 99%

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Determinants of public T cell responses

et al. 2012

Cell Res

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112

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Historically, sharing T cell receptors (TCRs) between individuals has been speculated to be impossible, considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual. However, public T cell response, in which multiple individuals share identical TCRs in responding to a same antigenic epitope, has been extensively observed in a variety of immune responses across many species. Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens, leading to favorable biological outcomes. However, the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens. It could be a great benefit for human health if public T cell responses can be manipulated. Therefore, the mechanistic insight of public TCR generation is important to know. Recently, high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires, which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals. Here, we summarize the current knowledge on public T-cell response and discuss future challenges in this field.

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Section: Recombinatorial Biasesmentioning

confidence: 62%

Section: The Role Of Thymic Selection In Tcr Sharingmentioning

confidence: 99%

Section: Future Challengesmentioning

confidence: 99%

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Determinants of public T cell responses

et al. 2012

Cell Res

113

112

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“…Hence, public TCR reported in the literature may have a probabilistic advantage to expand after antigenic stimulation simply because they belong to highly represented V-J rearrangement combinations. In another set of experiments, T-cell repertoires were compared in either genetically related or unrelated adult donors by flow cytometry [30]. These investigators confirmed a limited role of HLA haplotype and of the environment in shaping the T-cell repertoire.…”

Section: Discussionmentioning

confidence: 83%

“…Regarding clustering of the hTRBV genes, three major groups were observed (Fig. 4A, vertical dendrogram): the distribution of J elements within BV15,18,25,10,29,24,30 These are not the final page numbers (C6, C12, PBMC3, PBMC5, C10, C13, C14, C4, C11, C7 and C8), the other half being closer to the mean. The second group showed perturbation in the distribution of J elements within BV16, 14 and 13 across all samples.…”

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confidence: 99%

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Pham

Manuel²,

Petit

et al. 2011

Eur J Immunol

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In humanized mice, the T-cell repertoire is derived from genetically identical human progenitors in distinct animals. Thus, careful comparison of the T-cell repertoires of humanized mice with those of humans may reveal the contribution of genetic determinism on T-cell repertoire formation. Here, we performed a comprehensive assessment of the distribution of V-J combinations of the human b chain of the T-cell receptor (hTRBV) in NOD.SCID.cc À/À (NSG) humanized mice. We observed that numerous V-J combinations were equally distributed in the thymus and in the periphery of humanized mice compared with human references. A global analysis of the data, comparing repertoire perturbation indices in humanized NSG mice and unrelated human PBMCs, reveals that 50% of the hTRBV families significantly overlapped. Using multivariate ranking and bootstrap analyses, we found that 18% of all possible V-J combinations contributed close to 50% of the expressed diversity, with significant over-representation of BV5-J1.111.2 and BV6-J1.111.2 rearrangements. Finally, comparison of CD3 À and CD3 1 thymocyte repertoires indicated that the observed V-J combination overlap was already present before TCR-MHC selection in the thymus. Altogether, our results show that half of the T-cell repertoire combinatorial diversity in humans is genetically determined.Key words: Humanized mice . ISEApeaks . Multivariate score . T-cell repertoire . V-J rearrangements Supporting Information available online Introduction T-cell repertoire diversity is based upon tightly ordered genetic rearrangements of the T-cell receptor V, D and J genes. The available numbers of these genes in the genome constitutes a first level of diversity: to date, 33 and 65 genes encoding variable elements of the human T-cell receptor b chain (hTRBV) from 30 hTRBV families have been characterized in mice and humans respectively (according to the ImMunoGeneTics (IMGT) database (http://www.imgt.org)). An additional level of diversity comes from the association of single V, (D) and J elements together. The major determinant of repertoire diversity is then random addition of nucleotides at the junction of these V(D)J gene segments, constituting the CDR3 of the TCR. Finally, a fourth level of complexity originates from the association of the rearranged a and b chains of the TCR. In theory, these sequential processes occurring during T-cell differentiation in the thymus could Eur. J. Immunol. 2012. 42: 760-770 760 generate up to 10 15 different TCRs, a number far in excess of the number of T-cells in the body. The 'real' size of the repertoire is probably much lower though, with recent estimations of unique TCR b chains ranging from 10 6 to 4.10 6 in humans [1,2]. Mice reconstituted with a human immune system generated from hematopoietic precursors represent a new animal model for human immunology studies. The extent of the human T-cell repertoire diversity generated in mice may represent an important functional indicator [3], useful for immunological studies in the models. However, a...

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