γδ-T cells and αβ-TCR transduced γδ-T cells
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ABSTRACT:
PROVIDER: PRJNA896102 | ENA |
REPOSITORIES: ENA
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Project description:Notch-dependent BCL11B induction converts thymus seeding precursor cells into committed T cell progenitors that subsequently differentiate into T cells bearing either the γδ or αβ T cell receptor. In human, strong Notch activation favors γδ T cell development at the expense of αβ-lineage differentiation, but the underlying molecular mechanism has remained unclear. Therefore, we performed paired mRNA and miRNA profiling across 11 stages of human T cell development, including developing γδ T cells. We identify the miR-17-92 cluster as a direct Notch target and show that miR-17 promotes human TCRγδ T cell development by targeting BCL11B, a gene required for αβ but not for γδ T cell development. Thus, following its role as a licensing factor to induce BCL11B expression in early T cell precursors, Notch activation limits BCL11B expression through miR-17 until thymocytes have passed the β-selection checkpoint when Notch activation is turned off. Hereby Notch prevents premature BCL11B upregulation that is required for αβ-lineage differentiation and this results in preferential γδ-lineage differentiation. Our work unravels a dual role for Notch in controlling BCL11B expression during intrathymic differentiation and provides a unique resource for understanding the mRNA/miRNA interactions that control human T cell development. We used microarrays in order to profile the gene expression in 11 ex vivo T cell subsets, isolated from human thymus. Cord blood CD34+Lin- HPCs were used as a reference subset for extrathymic HPCs.
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Project description:Notch-dependent BCL11B induction converts thymus seeding precursor cells into committed T cell progenitors that subsequently differentiate into T cells bearing either the γδ or αβ T cell receptor. In human, strong Notch activation favors γδ T cell development at the expense of αβ-lineage differentiation, but the underlying molecular mechanism has remained unclear. Therefore, we performed paired mRNA and miRNA profiling across 11 stages of human T cell development, including developing γδ T cells. We identify the miR-17-92 cluster as a direct Notch target and show that miR-17 promotes human TCRγδ T cell development by targeting BCL11B, a gene required for αβ but not for γδ T cell development. Thus, following its role as a licensing factor to induce BCL11B expression in early T cell precursors, Notch activation limits BCL11B expression through miR-17 until thymocytes have passed the β-selection checkpoint when Notch activation is turned off. Hereby Notch prevents premature BCL11B upregulation that is required for αβ-lineage differentiation and this results in preferential γδ-lineage differentiation. Our work unravels a dual role for Notch in controlling BCL11B expression during intrathymic differentiation and provides a unique resource for understanding the mRNA/miRNA interactions that control human T cell development. The expression of 756 miRNAs was determined using the Taqman stem-loop RT-qPCR method as previously described (Mets E. Leukemia. 2015, Mavrakis KJ. Nat Genet. 2011).
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