Project description:Thymocyte differentiation is a complex process which involves well-defined sequential developmental stages that finally result in the generation of mature αβ and γδ T cells. Here, we analyzed DNA methylation and gene expression profiles at successive human thymus developmental stages from early T-cell progenitors to single positive (SP) CD4+ and CD8+ subpopulations

2014-12-30 | GSE55111 | GEO

DNA METHYLATION DURING αβ T CELL DEVELOPMENT IN THE HUMAN THYMUS [expression]

2014-12-30 | GSE54996 | GEO

Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development [BCL11B_ex vivo]

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.

2020-05-26 | GSE129852 | GEO

BCL6 is required for the thymic development of TCRαβ+CD8αα+ intraepithelial lymphocyte lineage

Project description:TCRαβ+CD8αα+ intraepithelial lymphocytes (CD8αα+ αβ IELs), a specialized subset of T cells in the gut epithelium, develop from thymic agonist-selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that Bcl6 deficiency in αβ T cells resulted in nearly the absence of CD8αα+ αβ IELs. BCL6 was expressed by approximately 50% of CD8αα+ αβ IELs but the majority thymic PD1+ IELps post agonist selection; its deficiency blocked early IELp generation in the thymus. Moreover, BCL6 expression in IELps was induced by thymic TCR signaling in an ERK-dependent manner. As a result of Bcl6 deficiency, the precursors of IELps among CD4+CD8+ double positive (DP) thymocytes exhibited increased apoptosis during agonist selection, and impaired IELp differentiation and maturation. Taken together, our results elucidate BCL6 as a crucial transcription factor during the thymic development of CD8αα+ αβ IELs.

2024-02-26 | GSE248163 | GEO

Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development [miRNA BCL11B_ex vivo]

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 and 3 small RNA controls was determined using the Taqman stem-loop RT-qPCR method as previously described (Mets E. Leukemia. 2015, Mavrakis KJ. Nat Genet. 2011).

2020-05-26 | GSE129854 | GEO

Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development [BCL11B_coculture]

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 gene expression in CD34+ thymocytes before culture and after 5 or 10 days culture on OP9 stromal cells expressing Notch ligands JAG1, JAG2, DLL1 or DLL4.

2020-05-26 | GSE129853 | GEO

Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development [miRNA BCL11B_coculture]

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).

2020-05-26 | GSE129855 | GEO

Homo sapiens

Project description:DNA methylation dynamics during early human development

| PRJDB4030 | ENA