The human fetal thymus generates effector invariant γδ T cells in a Lin28b-dependent manner
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ABSTRACT:
PROVIDER: PRJNA526634 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8713470_1.fastq.gz | Fastqsanger.gz | |||
| SRR8713470_2.fastq.gz | Fastqsanger.gz | |||
| SRR8713480_1.fastq.gz | Fastqsanger.gz | |||
| SRR8713480_2.fastq.gz | Fastqsanger.gz | |||
| SRR8713471_1.fastq.gz | Fastqsanger.gz |
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Project description:In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming can occur in human is not known. Here we analyzed human fetal and post-natal γδ thymocytes and investigated the role of hematopoietic-stem-and-precursor-cells (HSPC) in the generation of human γδ T cells. Unlike post-natal γδ thymocytes, fetal γδ thymocytes were functionally programmed (e.g. IFNγ, granzymes), expressed low levels of terminal-deoxynucleotidyl-transferase (TdT) and were highly enriched for invariant/public germline-encoded CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY and TRDV1-TRDD3-CALGELGD, previously shown to be expanded in cytomegalovirus infection) composed of short-homology-repeat-containing gene segments. Furthermore, these unique characteristics were due to an intrinsic property of fetal HSPC caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in a HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.
2019-11-21 | GSE128163 | GEO
Project description:TCR γ chain loci of mice have seven variable (Vγ) gene segments (Vγ1, Vγ2, Vγ3, Vγ4, Vγ5, Vγ6, and Vγ7) using the Heilig and Tonegawa nomenclature. Vγ6+ γδ T cells, which develop in the thymus at the perinatal stage, are distributed within the mucosal tissues in the periphery. Vγ6+ γδ T cells are exclusive interleukin (IL)-17 producers among γδ T cells, and Vγ6+ IL-17A+ γδ T (γδT17) cells play important roles in protection against microbial infection and in the pathogenesis of inflammatory diseases, such as colitis and autoimmune diseases. We have previously reported that γδT17 cells develop from the CD4–CD8– (DN)2b stage in the thymus at the prenatal stage in a Bcl11b-dependent manner. However, details of the development of Vγ6+ γδT17 cells remain obscure. To analyze Vγ6+ γδ T cells in detail, we recently developed a monoclonal antibody (mAb; termed 1C10-1F7) specific to mouse Vg6 chain. Use of this mAb revealed that Vγ6+ γδ T cells in 0-day-old thymus were co-localized with medullary thymic epithelial cells (mTECs), which regulate T cell tolerance by self-antigen presentation using major histocompatibility complex (MHC) class II. Here, we report that MHC class II in the thymus inhibits the generation of Vγ6+ γδT17 cells.
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Project description:In the mouse thymus, invariant ?? T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming and age-dependent generation of invariant ?? T cells occur in humans is not known. Here we found that, unlike postnatal ?? thymocytes, human fetal ?? thymocytes were functionally programmed (e.g., IFN?, granzymes) and expressed low levels of terminal deoxynucleotidyl transferase (TdT). This low level of TdT resulted in a low number of N nucleotide insertions in the complementarity-determining region-3 (CDR3) of their TCR repertoire, allowing the usage of short homology repeats within the germline-encoded VDJ segments to generate invariant/public cytomegalovirus-reactive CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY, and TRDV1-TRDD3-CALGELGD). Furthermore, both the generation of invariant TCRs and the intrathymic acquisition of effector functions were due to an intrinsic property of fetal hematopoietic stem and precursor cells (HSPCs) caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in an HSPC/Lin28b-dependent manner, invariant ?? T cells with programmed effector functions.
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