Lin28b controls a neonatal to adult switch in B cell positive selection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA559395 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9935810_1.fastq.gz | Fastqsanger.gz | |||
| SRR9935810_2.fastq.gz | Fastqsanger.gz | |||
| SRR9935801_1.fastq.gz | Fastqsanger.gz | |||
| SRR9935801_2.fastq.gz | Fastqsanger.gz | |||
| SRR9935811_1.fastq.gz | Fastqsanger.gz |
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Project description:The ability of B-1 cells to become positively selected into the mature B cell pool, despite being weakly self-reactive, has puzzled the field since its initial discovery. Here, we explore changes in B cell positive selection as a function of developmental time by exploiting a link between CD5 surface levels and the natural occurrence of self-reactive B cell receptors (BCRs) in BCR wildtype mice. We show that the heterochronic RNA-binding protein Lin28b potentiates a neonatal mode of B cell selection characterized by enhanced overall positive selection and the developmental progression of CD5+ immature B cells in particular. Importantly, Lin28b achieves this through amplifying the CD19/PI3K/c-Myc positive feedback loop and ectopic Lin28b expression restores both positive selection and mature B cell numbers in CD19–/– adult mice. Thus, the temporally restricted expression of Lin28b alters the rules for B cell selection during ontogeny through modulating tonic signaling. We propose that this neonatal mode of B cell selection represents a cell intrinsic cue to accelerate the de novo establishment of the adaptive immune system and incorporate a layer of natural antibody mediated immunity throughout life.
2019-08-27 | GSE135603 | GEO
Project description:Developing B cells can differentiate into a variety of different subsets, but the mechanisms that determine these outcomes are incompletely understood, with theories based on separate lineages or the positive and negative selection by self-antigens. In particular, the development of the B-1 B cell subset arises mainly from precursors in early ontogeny and is subject to positive selection by self-antigens, whereas the follicular B-2 B cell subset arises later and is subject to negative control. In this study we show how a cell intrinsic switch from Lin28b to Let7 gene expression changes a B cell’s susceptibility from positive to negative selection during ontogeny. Ectopic expression of a Lin28b transgene in B cells restores the positive selection of autoreactive B-1 B cells by self-antigen in adult bone marrow. Analysis of antigen-specific immature B cells in early and late ontogeny identifies Lin28b-dependent genes associated with B-1 B cell development, including Arid3a and Bhleh41, and Lin28b-independent effects associated with the presence or absence of self-antigen. These findings identify cell intrinsic and extrinsic determinants of B cell fate during ontogeny and reconcile lineage and selection theories of B cell development. They explain how changes in the balance of positive and negative selection may be able to adapt to meet the immunological needs of an individual during its lifetime.
2020-02-26 | GSE135648 | GEO
Project description:Developing B cells can differentiate into a variety of different subsets, but the mechanisms that determine these outcomes are incompletely understood, with theories based on separate lineages or the positive and negative selection by self-antigens. In particular, the development of the B-1 B cell subset arises mainly from precursors in early ontogeny and is subject to positive selection by self-antigens, whereas the follicular B-2 B cell subset arises later and is subject to negative control. In this study we show how a cell intrinsic switch from Lin28b to Let7 gene expression changes a B cell’s susceptibility from positive to negative selection during ontogeny. Ectopic expression of a Lin28b transgene in B cells restores the positive selection of autoreactive B-1 B cells by self-antigen in adult bone marrow. Analysis of antigen-specific immature B cells in early and late ontogeny identifies Lin28b-dependent genes associated with B-1 B cell development, including Arid3a and Bhleh41, and Lin28b-independent effects associated with the presence or absence of self-antigen. These findings identify cell intrinsic and extrinsic determinants of B cell fate during ontogeny and reconcile lineage and selection theories of B cell development. They explain how changes in the balance of positive and negative selection may be able to adapt to meet the immunological needs of an individual during its lifetime.
2020-02-26 | GSE135649 | GEO
Project description:Developing B cells can differentiate into a variety of different subsets, but the mechanisms that determine these outcomes are incompletely understood, with theories based on separate lineages or the positive and negative selection by self-antigens. In particular, the development of the B-1 B cell subset arises mainly from precursors in early ontogeny and is subject to positive selection by self-antigens, whereas the follicular B-2 B cell subset arises later and is subject to negative control. In this study we show how a cell intrinsic switch from Lin28b to Let7 gene expression changes a B cell’s susceptibility from positive to negative selection during ontogeny. Ectopic expression of a Lin28b transgene in B cells restores the positive selection of autoreactive B-1 B cells by self-antigen in adult bone marrow. Analysis of antigen-specific immature B cells in early and late ontogeny identifies Lin28b-dependent genes associated with B-1 B cell development, including Arid3a and Bhleh41, and Lin28b-independent effects associated with the presence or absence of self-antigen. These findings identify cell intrinsic and extrinsic determinants of B cell fate during ontogeny and reconcile lineage and selection theories of B cell development. They explain how changes in the balance of positive and negative selection may be able to adapt to meet the immunological needs of an individual during its lifetime.
2020-02-26 | GSE135224 | GEO
Project description:In this study, we identify elevated protein synthesis as a defining characteristic of early life B cell development and a determinant for the qualitative switch in B cell output whereby self-reactive CD5+ B-1 cells becomes censored in postnatal mice This is in part mediated by the heterochronic RNA binding protein LIN28B. To identify Lin28b-dependent, stage specific effects, B cell progenitors at different developmental stages were sorted and analyzed by RNA-seq
2022-11-16 | GSE217787 | GEO
Project description:In this study, we identify elevated protein synthesis as a defining characteristic of early life B cell development and a determinant for the qualitative switch in B cell output whereby self-reactive CD5+ B-1 cells becomes censored in postnatal mice This is in part mediated by the heterochronic RNA binding protein LIN28B. To identify Lin28b-dependent, stage specific effects, B cell progenitors at different developmental stages were sorted and analyzed by RNA-seq
2022-11-16 | GSE217786 | GEO
Project description:An ontogenetic switch in the positive and negative selection of B cells
| PRJNA559543 | ENA
Project description:An ontogenetic switch in the positive and negative selection of B cells [IgHEL]
| PRJNA559547 | ENA
Project description:Mouse B cell precursors from fetal liver and adult bone marrow generate distinctive B cell progeny when transplanted into immunodeficient recipients, supporting a two-pathway model for B lymphopoiesis, fetal “B-1” and adult “B-2”. Recently Lin28b was shown to be important for the switch between fetal and adult pathways; however, neither the mechanism of Lin28b action nor the importance of BCR signaling in this process was addressed. Here we report important advances in our understanding of the regulation of B 1/B-2 development. First, modulation of Let-7 in fetal Pro-B cells is sufficient to alter fetal B-1 development to produce B cells resembling the progeny of adult B-2 development. Second, intact BCR signaling is required for generation of B1a B cells from Lin28b-transduced bone marrow progenitors, supporting a requirement for ligand-dependent selection, as is the case for normal B1a B cells. Third, the VH repertore of Lin28b-induced bone marrow B1a B cells differs from that of normal B1a. Finally we identify the Arid3a transcription factor as a key target of Let-7, whose ectopic expression is sufficient to induce B-1 development in adult Pro-B cells and whose knockdown blocks B-1 development in fetal Pro-B cells. 2 individual sorts of bone marrow Pro-B cells 4 days after Lin28b retroviral transduction (and 2 sorts of empty vector control) and 2 individual sorts of fetal liver Pro-B cells 4 days after Let-7b retroviral transduction (and 2 sorts of empty vector controls).
2015-03-01 | E-GEOD-65534 | biostudies-arrayexpress
Project description:Mouse B cell precursors from fetal liver and adult bone marrow generate distinctive B cell progeny when transplanted into immunodeficient recipients, supporting a two-pathway model for B lymphopoiesis, fetal “B-1” and adult “B-2”. Recently Lin28b was shown to be important for the switch between fetal and adult pathways; however, neither the mechanism of Lin28b action nor the importance of BCR signaling in this process was addressed. Here we report important advances in our understanding of the regulation of B 1/B-2 development. First, modulation of Let-7 in fetal Pro-B cells is sufficient to alter fetal B-1 development to produce B cells resembling the progeny of adult B-2 development. Second, intact BCR signaling is required for generation of B1a B cells from Lin28b-transduced bone marrow progenitors, supporting a requirement for ligand-dependent selection, as is the case for normal B1a B cells. Third, the VH repertore of Lin28b-induced bone marrow B1a B cells differs from that of normal B1a. Finally we identify the Arid3a transcription factor as a key target of Let-7, whose ectopic expression is sufficient to induce B-1 development in adult Pro-B cells and whose knockdown blocks B-1 development in fetal Pro-B cells.
2015-03-01 | GSE65534 | GEO