Allelic Exclusion at the TCRδ Locus and Commitment to γδ Lineage: Different Modalities Apply to Distinct Human γδ Subsets

Couedel, Chrystelle; Lippert, Éric; Bernardeau, Karine; Bonneville, Marc; Davodeau, François

doi:10.4049/jimmunol.172.9.5544

Cited by 14 publications

(16 citation statements)

References 47 publications

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“…However our data indicates that both TCRγ alleles rearrange in the majority of T cells, in agreement with the prior published data (38). Other evidence also suggests that TCRγ rearranges prior to the cell fate determination and, therefore, prior to thymic selection (18, 36).…”

Section: Discussionsupporting

confidence: 94%

Deep Sequencing of the Human TCRγ and TCRβ Repertoires Suggests that TCRβ Rearranges After αβ and γδ T Cell Commitment

et al. 2011

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The two main lineages of T lymphocytes develop from multi potent precursors in the human thymus. The most common type in blood are αβ T cells, which bind to antigenic peptides displayed on the surface of cells by human leukocyte antigen (HLA) molecules. Far less well understood are γδ T cells, which do not bind HLA: peptide complexes and are more prevalent in the gut mucosa. For both lineages, their ability to recognize a diverse array of antigens is mediated by a rearranged Y-like receptor on their surface, the T cell receptor (TCR), composed and of an α and β chain for αβ T cells or a γ and δ chain for γδ T cells. The canonical model for commitment from the precursor to one these two lineages assumes that γ, δ, and β chains rearrange prior to commitment to αβ or γδ T cells. A crucial step towards better understanding the role of γδ T cells is to work out the developmental process. To test the standard model and to understand the γδ TCR repertoire, we use high-throughput sequencing to catalog millions of TCRγ and TCRβ chains from peripheral blood αβ and γδ T cells, from three unrelated individuals. Almost all sampled αβ and γδ T cells have rearranged TCRγ sequences. While sampled αβ T cells have a diverse repertoire of rearranged TCRβ chains, less than 10% of γδ T cells in peripheral blood have a rearranged TCRβ chain. Our data indicate that TCRγ rearranges in all T lymphocytes, consistent with TCRγ rearranging prior to T cell lineage commitment, while rearrangement of the TCRβ locus is restricted, and occurs after T cell precursors commit to the αβ T cell lineage. This result explains the conundrum in T cell leukemia and lymphoma that TCRγ is almost always rearranged and TCRβ is only rearranged in a subset of cancers. As high-throughput sequencing of TCRs is translated into the clinic for monitoring minimal residual for leukemia/lymphoma, our data suggests the sequencing target needs to be TCR γ.

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Section: Discussionsupporting

confidence: 94%

Deep Sequencing of the Human TCRγ and TCRβ Repertoires Suggests that TCRβ Rearranges After αβ and γδ T Cell Commitment

et al. 2011

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“…We did find extensive D3 J␤ rearrangements in human ␥␦ cells (data not shown), indicating that early on, at least part of the TCR␤ locus was accessible to the recombination machinery. Our data are consistent with those of Couedel et al (53) who showed that cloned peripheral blood ␥␦ T cells contained a low percentage of complete V3 DJ␤ rearrangements. Second, and more importantly, the few complete ␤ rearrangements detected were predominately out-of-frame (Table III), suggesting an instructional role for the pre-TCR in diversion away from the ␥␦ lineage.…”

Section: Discussionsupporting

confidence: 83%

Human αβ and γδ Thymocyte Development: TCR Gene Rearrangements, Intracellular TCRβ Expression, and γδ Developmental Potential—Differences between Men and Mice

Joachims

Chain

Hooker

et al. 2006

The Journal of Immunology

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To evaluate the role of the TCR in the αβ/γδ lineage choice during human thymocyte development, molecular analyses of the TCRβ locus in γδ cells and the TCRγ and δ loci in αβ cells were undertaken. TCRβ variable gene segments remained largely in germline configuration in γδ cells, indicating that commitment to the γδ lineage occurred before complete TCRβ rearrangements in most cases. The few TCRβ rearrangements detected were primarily out-of-frame, suggesting that productive TCRβ rearrangements diverted cells away from the γδ lineage. In contrast, in αβ cells, the TCRγ locus was almost completely rearranged with a random productivity profile; the TCRδ locus contained primarily nonproductive rearrangements. Productive γ rearrangements were, however, depleted compared with preselected cells. Productive TCRγ and δ rearrangements rarely occurred in the same cell, suggesting that αβ cells developed from cells unable to produce a functional γδ TCR. Intracellular TCRβ expression correlated with the up-regulation of CD4 and concomitant down-regulation of CD34, and plateaued at the early double positive stage. Surprisingly, however, some early double positive thymocytes retained γδ potential in culture. We present a model for human thymopoiesis which includes γδ development as a default pathway, an instructional role for the TCR in the αβ/γδ lineage choice, and a prolonged developmental window for β selection and γδ lineage commitment. Aspects that differ from the mouse are the status of TCR gene rearrangements at the nonexpressed loci, the timing of β selection, and maintenance of γδ potential through the early double positive stage of development.

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“…In humans, the earliest thymic progenitors (CD34+CD1a−) have a rearranged Tcrd locus, while the Tcrb locus remains in germline configuration [26]. Additionally, partial allelic exclusion is evident at the Tcrg locus [27], indicating that γ chains are pairing with preexisting δ chains. …”

Section: γ δ T Cell Developmentmentioning

confidence: 99%

Repertoire Development and the Control of Cytotoxic/Effector Function in Human γδ T Cells

Urban

Chapoval

Pauza

2010

Journal of Immunology Research

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T cells develop into two major populations distinguished by their T cell receptor (TCR) chains. Cells with the α β TCR generally express CD4 or CD8 lineage markers and mostly fall into helper or cytotoxic/effector subsets. Cells expressing the alternate γ δ TCR in humans generally do not express lineage markers, do not require MHC for antigen presentation, and recognize nonpeptidic antigens. We are interested in the dominant Vγ2Vδ2+ T cell subset in human peripheral blood and the control of effector function in this population. We review the literature on γ δ T cell generation and repertoire selection, along with recent work on CD56 expression and defining a cytotoxic/effector lineage within the phosphoantigen-reactive Vγ2Vδ2 cells. A unique mechanism for MHC-independent repertoire selection is linked to the control of effector function that is vital to the role for γ δ T cells in tumor surveillance. Better understanding of these mechanisms will improve our ability to exploit this population for tumor immunotherapy.

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Allelic Exclusion at the TCRδ Locus and Commitment to γδ Lineage: Different Modalities Apply to Distinct Human γδ Subsets

Cited by 14 publications

References 47 publications

Deep Sequencing of the Human TCRγ and TCRβ Repertoires Suggests that TCRβ Rearranges After αβ and γδ T Cell Commitment

Deep Sequencing of the Human TCRγ and TCRβ Repertoires Suggests that TCRβ Rearranges After αβ and γδ T Cell Commitment

Human αβ and γδ Thymocyte Development: TCR Gene Rearrangements, Intracellular TCRβ Expression, and γδ Developmental Potential—Differences between Men and Mice

Repertoire Development and the Control of Cytotoxic/Effector Function in Human γδ T Cells

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