Analysis of murine neonatal Germinal Center (GC) B cells transcriptome (RNA-Seq) following HA/CAF01 immunization in the presence or absence of maternal antibodies
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ABSTRACT:
PROVIDER: PRJNA518898 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8521750.fastq.gz | Fastqsanger.gz | |||
| SRR8521741.fastq.gz | Fastqsanger.gz | |||
| SRR8521751.fastq.gz | Fastqsanger.gz | |||
| SRR8521742.fastq.gz | Fastqsanger.gz | |||
| SRR8521752.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: the goals of this study are to characterize GC B cells elicited by neonatal immunization with HA/CAF01 at the transcriptome level (RNA-seq) and study whether and how maternal antibodies affect GC B cell differentiation in early life Methods: transcriptomic analysis of highly pure GC B cells and the corresponding non-GC B cells isolated from draining lymph nodes of immunized neonatal mice were generated by HiSeq 4000 sequencing, using Illumina Technology. The sequence reads that passed quality filters were analyzed using the package edgeR: the fold-change and the Benjamini-Hochberg corrected p-value thresholds were set to 2 and 0.05 respectively. Main results: 1) we identified the differentially expressed genes (DEGs) in GC B cells versus non-GC B cells in murine neonates born to naive or influenza-immune mothers and observed that the canonical changes reflecting the acquisition of a GC B cell phenotype and state after neonatal immunization are not affected by high titers of maternal antibodies. 2) 39 DEGs distinguished GC B cells elicited in the presence or absence of MatAbs. GC B cells elicited in presence or absence of MatAbs used different VH and Vk genes and showed differences in genes associated with B cell differentiation and isotype switching.
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Project description:Selection of B cells subjected to hypermutation in germinal centres (GC) during T-dependent (TD) antibody responses yields memory cells and long-lived plasma cells that produce high affinity antibodies biased to foreign antigens rather than self-antigens. GC also form in T-independent (TI) responses to polysaccharide antigens but failed selection results in GC involution and memory cells are not generated. To date there are no markers that allow phenotypic distinction of T-dependent and T-independent germinal centre B cells. We have now compared the global gene expression of GC B cells purified from mice immunized with either TD or TI antigens and identified eighty genes that are differentially expressed in TD GC. Experiment Overall Design: QMxB6 F1 mice were immunised with T-independent antigens (NP-Ficoll) or T-dependent antigens (NP-CGG). T-dependent responses were analysed in carrier primed mice and non-carrier primed mice. The kinetics in carrier primed mice are comparable to those of TI-2 antigens, and thus, both of these groups were analysed 4 days after immunization with soluble antigen. The response in non-carrier primed mice peaks later, and was therefore analysed on day 10 after immunization. Germinal centre B cells were MACS enriched and then FACS sorted according to GL-7 and B220 expression. Sorted B cells from the relevant mice were pooled (4-10 mice per sample). Each sample thus contains B cells from different mice, and the replicates are biological, not technical replicates.
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Project description:Long-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. It has been proposed that high affinity cells are preferentially selected into this compartment, potentiating the immune response. We used single cell RNA-seq to track the germinal center (GC) development of Ighg2A10 cells, specific for the Plasmodium falciparum circumsporozoite protein (PfCSP). Following immunization with Plasmodium sporozoites we identified 3 populations of cells in the GC light zone. One population expressed a gene signature associated with the initiation of PC differentiation and had an enhanced propensity to form PCs in vitro. Unexpectedly, the estimated affinity of this putative pre-PC population was indistinguishable from cells in the GC generally. This was also true when high- or low-avidity recombinant PfCSP proteins were used as immunogens. Immunization with low-avidity PfCSP did, however, induce increased affinity maturation. Collectively these findings suggest that the initiation of PC development in the GC occurs via an affinity independent process.
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Project description:Long-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. It has been proposed that high affinity cells are preferentially selected into this compartment, potentiating the immune response. We used single cell RNA-seq to track the germinal center (GC) development of Ighg2A10 cells, specific for the Plasmodium falciparum circumsporozoite protein (PfCSP). Following immunization with Plasmodium sporozoites we identified 3 populations of cells in the GC light zone. One population expressed a gene signature associated with the initiation of PC differentiation and had an enhanced propensity to form PCs in vitro. Unexpectedly, the estimated affinity of this putative pre-PC population was indistinguishable from cells in the GC generally. This was also true when high- or low-avidity recombinant PfCSP proteins were used as immunogens. Immunization with low-avidity PfCSP did, however, induce increased affinity maturation. Collectively these findings suggest that the initiation of PC development in the GC occurs via an affinity independent process.
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Project description:Germinal centers (GCs) are the engines of antibody evolution. Using HIV Env protein immunogen priming in rhesus monkeys (RM) followed by a long period without further immunization, we demonstrate GC B cells (BGC) lasted at least 6 months. A 186-fold BGC cell increase was present by week 10 compared to a conventional immunization. Single cell transcriptional profiling revealed both light and dark zone GC states were sustained. Antibody somatic hypermutation (SHM) of BGC cells continued to accumulate throughout the 29-week priming period, with evidence of selective pressure. Env-binding BGC cells were still 49-fold above baseline at 29 weeks, suggesting they could be active for even longer periods of time. High HIV neutralizing antibody titers were generated after a single booster immunization. Fully glycosylated HIV trimer protein is a complex antigen, posing significant immunodominance challenges for B cells. Memory B cells (BMem) generated under these long priming conditions had higher levels of SHM, and both BMem cells and antibodies were more likely to recognize non-immunodominant epitopes. Numerous BGC cell lineage phylogenies spanning the >6-month GC period were identified, demonstrating continuous GC activity and selection for at least 191 days with no additional antigen exposure. A long prime, slow delivery (12-day) immunization approach holds promise for difficult vaccine targets, and suggests that patience can have great value for tuning GCs to maximize antibody responses.
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Project description:Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The formation of GCs has been studied in detail, but less is known about what leads to their regression and eventual termination, factors that ultimately limit the extent to which antibodies mature within a single reaction. We show that contraction of immunization-induced GCs is immediately preceded by an acute surge in GC-resident Foxp3+ T cells, attributed at least partly to upregulation of the transcription factor Foxp3 by T follicular helper (Tfh) cells. Ectopic expression of Foxp3 in Tfh cells is sufficient to decrease GC size, implicating the natural upregulation of Foxp3 by Tfh cells as a potential regulator of GC lifetimes.
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