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Human αβ and γδ Thymocyte Development: TCR Gene Rearrangements, Intracellular TCRβ Expression and γδ Developmental Potential – Differences between Men and Mice,
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 co...
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| Main Authors: | , , , , |
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| Formato: | Artigo |
| Idioma: | English |
| Publicado em: |
2006
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| Assuntos: | |
| Acesso em linha: | https://ncbi.nlm.nih.gov/pmc/articles/PMC1592528/ https://ncbi.nlm.nih.gov/pubmed/16424183 |
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| Resumo: | 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 prior to 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 non-productive rearrangements. Productive γ rearrangements were, however, depleted compared to pre-selected 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 non-expressed loci, the timing of β-selection, and maintenance of γδ potential through the early double positive stage of development. |
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