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B cell-intrinsic IFN-g promotes CD11c+ age-associated B cell differentiation and compromises affinity-based germinal center selection in lupus

ABSTRACT: B cell-intrinsic IFN-g promotes CD11c+ age-associated B cell differentiation and compromises affinity-based germinal center selection in lupus

PROVIDER: PRJNA1132944 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29734579_1.fastq.gz	Fastqsanger.gz
	SRR29734579_2.fastq.gz	Fastqsanger.gz

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B cell-intrinsic IFN-g promotes CD11c+ age-associated B cell differentiation and compromises affinity-based germinal center selection in lupus

Project description:Lupus patients respond less efficiently to vaccinations and are more susceptible to infections. Previously, we have shown, in lupus models, that excessive CD11c+ age-associated B cells (ABCs) not only contribute to autoantibody production but also compromise antigen-specific germinal center (GC) B cell selection and affinity maturation by promoting aberrant T cell activation. Yet, how CD11c+ ABC differentiation is regulated is not fully understood. Here we show that B cell-intrinsic IFN-γ is required for excessive CD11c+ ABC differentiation in lupus mice. B cell-intrinsic IFN-γ is mainly produced by CD11c+ ABCs. IFN-γ-deficiency leads to decreased expression of ABC characteristic genes, including Zeb2, an ABC-specific transcription factor recently described. We further show that ablating IFN-γ can normalize T cell overactivation and rescue antigen-specific GC responses in lupus mice. Our study offers insight into the crucial role of B cell-intrinsic IFN-γ in promoting CD11c+ ABC differentiation and compromising affinity-based germinal center selection and affinity maturation in lupus, providing a potential target for lupus treatment.

2024-07-13 | GSE271698 | GEO

Role of affinity in plasma cell development in the germinal center light zone

Project description:Protective immune responses to many pathogens depend on the development of high affinity antibody-producing plasma cells in germinal centers. Transgenic models suggest that there is a stringent affinity-based barrier to plasma cell development. Whether a similar high affinity barrier regulates plasma cell development under physiologic circumstances, and the nature of the plasma cell fate decision has not been defined precisely. Here we use a fate mapping approach to examine the relationship between germinal center (GC) B cells selected to undergo additional rounds of affinity maturation, germinal center pre-plasma cells and plasma cells. The data show that initial plasma cell selection overlaps with germinal center B cell selection, but that the plasma cell compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-plasma cell selection sieves the germinal center to enable accumulation of a more restricted group of high affinity antibody secreting plasma cells.

2023-11-02 | GSE246382 | GEO

Lung B cells in ectopic germinal centres undergo affinity maturation

Project description:Lung B cells in ectopic germinal centres undergo affinity maturation

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Lung B cells in ectopic germinal centres undergo affinity maturation

Project description:Chronic exposure to allergens and other airborne antigens can result in the formation of lymphocyte aggregates in the lung, which can harbour ectopic germinal centres (GCs). After allergen exposure, GCs that form in the lung are much smaller and less densely packed with B cells than lymph node GCs. Despite this, ectopic lung GCs can support somatic hypermutation and affinity-based maturation as in lymph node GCs, and can export memory B cells directly into the lung tissue. This demonstrates that the lung itself can locally diversify B cell responses and support the generation of tissue memory B cell populations in situ. Here, we have employed a single cell sequencing approach using 10x Genomics scRNAseq and BCRseq to study germinal centre B cell clonal sharing between the mediastinal lymph node and lungs of mice.

2025-02-27 | GSE286951 | GEO

Long primed germinal centers with enduring affinity maturation and clonal migration

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Lack of affinity signature for germinal center cells that have initiated plasma cell differentiation (Figure2)

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.

2024-01-15 | GSE227370 | GEO

Lack of affinity signature for germinal center cells that have initiated plasma cell differentiation (Figure4)

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Isotype switching in human memory B cells sets intrinsic antigen-affinity thresholds that dictate antigen-driven fates

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2023-10-25 | GSE215788 | GEO

Csk restrains BCR-mediated ROS production and contributes to germinal center selection and affinity maturation

Project description:Compared with naïve B cells, the B cell receptor (BCR) signal in germinal center (GC) B cells is attenuated; however, the significance of this signaling attenuation has not been well defined. Here, to investigate the role of attenuation of BCR signaling, we employed a Csk mutant mouse model in which Csk-deficiency in GC B cells resulted in augmentation of net BCR signaling with no apparent effect on antigen presentation. We found that Csk is required for GC maintenance and efficient antibody affinity maturation. Mechanistically, ROS-induced apoptosis was exacerbated concomitantly with mitochondrial dysfunction in Csk-deficient GC B cells. Hence, our data suggest that attenuation of the BCR signal restrains hyper-ROS production, thereby protecting GC B cells from apoptosis and contributing to efficient affinity maturation.

2024-05-06 | GSE244802 | GEO

Role of affinity in plasma cell development in the germinal center light zone

Project description:Role of affinity in plasma cell development in the germinal center light zone

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