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Myc transcriptional bursts promote B cell positive selection by T cells in germinal centers

ABSTRACT: Myc transcriptional bursts promote B cell positive selection by T cells in germinal centers

PROVIDER: PRJNA994027 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25244816.fastq.gz	Fastqsanger.gz
	SRR25244817.fastq.gz	Fastqsanger.gz
	SRR25244818.fastq.gz	Fastqsanger.gz
	SRR25244819.fastq.gz	Fastqsanger.gz
	SRR25244820.fastq.gz	Fastqsanger.gz

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Myc transcriptional bursts promote B cell positive selection by T cells in germinal centers

Project description:Antibody affinity maturation occurs in secondary lymphoid organs within germinal centers (GCs) where B cells mutate their antibody-encoding genes in the dark zone (DZ) followed by a selection of the high-affinity variants in the light zone (LZ) by T cells. The amount of the T cell-derived selection signals is proportional to the BCR affinity and the magnitude of Myc expression. However, since the lifetimes of Myc mRNA and protein are extremely short, it is unclear how high levels of Myc are maintained in the GC B cell to allow positive selection. Here, by measuring Myc transcripts in situ at the single-cell level, we find that T cell help promotes the frequency of Myc transcriptional bursts. T cell help primarily increases the number of Myc-positive cells rather than the amount of Myc per cell. Measurement of Myc intronic and exonic transcripts in situ demonstrates that positive selection is mediated by Myc transcriptional bursts through a rapid increase in the active transcription sites rather than an elevation in transcription rate or gene accessibility. Thus, the amount of Myc transcriptional bursts over time in the LZ, rather than Myc abundance, dictates B cell selection in germinal centers.

2024-10-15 | GSE237128 | GEO

The Ubiquitin Ligase Itch Skews Light Zone Selection in Germinal Centers

Project description:Ig diversification occurs in peripheral lymphoid organs after establishment of central tolerance during B cell development. In germinal centers (GCs), somatic hypermutation of Ig genes occurs in dark zones, followed by selection of mutated clones in light zones (LZs). This generates high-affinity Ig receptors to pathogens but can also produce autoreactive Ig receptors, which are removed by selection mechanisms that are incompletely understood. The ubiquitin ligase Itch prevents the emergence of autoimmune disease and autoantibodies in humans and mice, and patients lacking Itch develop potentially fatal autoimmune diseases; yet, how Itch regulates GC B cells is not well understood. By studying Itch-deficient mice, we have recently shown that Itch directly limits the magnitude of GC responses. Proteomic profiling of GC B cells uncovered that Itch-deficient cells exhibit high mTORC1 and Myc activity, hallmarks of positive selection. Bone marrow chimera and adoptive transfer experiments revealed that B cell Itch restricts noncycling LZ cells. These results support, t our knowledge, a novel role for Itch in skewing selection of GC B cells to restrict LZ accumulation and shape GC-derived humoral immunity. Determining how B cells integrate cues within GCs to navigate through LZs and dark zones will aid in understanding how autoreactive clones emerge from GCs in people with autoimmune disease.

2024-11-12 | PXD040978 | Pride

Comprehensive transcriptome characterization deciphers mechanisms underpinning the positive selection of B cells in germinal centers.

Project description:Comprehensive transcriptome characterization deciphers mechanisms underpinning the positive selection of B cells in germinal centers.

| PRJNA1168544 | ENA

B cell receptor signaling in germinal centers prolongs survival and primes B cells for selection [bulk RNA-seq]

Project description:Germinal centers (GCs) are sites of B cell clonal expansion, diversification, and antibody affinity selection. This process is limited and directed by T follicular helper cells that provide helper signals to B cells that endocytose, process, and present cognate antigens in proportion to their B cell receptor (BCR) affinity. Under this model, the BCR functions as an endocytic receptor for antigen capture. How signaling through the BCR contributes to selection is not well understood. To investigate the role of BCR signaling in GC selection, we developed a tracker for antigen binding and presentation and a Bruton’s tyrosine kinase drug-resistant-mutant mouse model. We showed that BCR signaling per se is necessary for the survival and priming of light zone B cells to receive T cell help. Our findings provide insight into how high-affinity antibodies are selected within GCs and are fundamental to our understanding of adaptive immunity and vaccine development.

2023-03-09 | GSE225573 | GEO

B cell receptor signaling in germinal centers prolongs survival and primes B cells for selection [single cell RNA-Seq]

2023-03-09 | GSE225574 | GEO

Proteome profiling of mouse germinal center B cells

Project description:Productive B cell responses are critical to protect a host from infection. The spleen and lymph nodes are populated by resting follicular B cells, which can enter germinal centers upon antigen encounter. Once in the germinal center, B cells migrate between the dark and light zones, where they undergo somatic hypermutation and selection, respectively. While germinal center B cells have been studied, an intense molecular understanding of these cells/subsets (and the differences between them) is lacking.

2020-04-06 | PXD015524 | Pride

Comprehensive transcriptome characterization deciphers mechanisms underpinning the positive selection of B cells in germinal centers. [mouse; short-read]

Project description:Alternative splicing (AS) and translational regulation play major roles in the activation and differentiation of immune cells. Previous studies using short-read sequencing linked individual AS events in germinal center (GC) B cells to proliferation and survival. To establish a more comprehensive understanding of transcript isoform changes that accompany B cell selection in the GC we developed a workflow for long-read nanopore sequencing. MYC expression by GC B cells marks cells undergoing a programme of AS which includes the removal of poison exons (PE) in splicing factors SRSF3 and SRSF7. These are crucial for B cell expansion and regulate transcripts encoding the translation machinery which is markedly increased upon positive selection of the GC B cell.

2024-10-04 | GSE278742 | GEO

Signatures of positive selection in germinal center B cells

Project description:We used RNA sequencing to characterize gene expression of Ly75+/+ B1-8hi and Ly75-/- B1-8hi B cells from the germinal center light zone (LZ) 12 h after forcing positive selection of the Ly75+/+ population with anti-DEC205-OVA.

2017-05-25 | GSE98778 | GEO

Comprehensive transcriptome characterization deciphers mechanisms underpinning the positive selection of B cells in germinal centers. [mouse short-read]

Project description:Comprehensive transcriptome characterization deciphers mechanisms underpinning the positive selection of B cells in germinal centers. [mouse short-read]

| PRJNA1168549 | ENA

B cell receptor signaling in germinal centers prolongs survival and primes B cells for selection

Project description:B cell receptor signaling in germinal centers prolongs survival and primes B cells for selection

| PRJNA936432 | ENA