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RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response[scRNA-seq]

ABSTRACT: B cells are crucial for adaptive immunity, orchestrating humoral responses by producing antibodies essential for pathogen clearance. Here, we show that Poly(rC) binding protein 1 (Pcbp1), a multifunctional RNA-binding protein, is a key regulator of antibody production in B cells. Pcbp1 deficiency in B cells resulted in significant reductions in IgM expression at steady state and compromised differentiation of germinal center B cells and production of high-affinity antibodies upon immunization. These effects result from compromised mitochondrial integrity in Pcbp1-deficient B cells, including compromised mitochondrial electron transport chain (ETC) complex I and increased mitochondrial ROS production. Blocking mitochondrial ROS production rescued IgM production and improved germinal center responses caused by Pcbp1 deficiency. Mechanistically, Pcbp1 promotes the expression of Fdxr, a critical component of ETC complex I, via binding to its 3’UTR. Overall, our findings reveal a novel role for Pcbp1 in regulating mitochondrial function, protein synthesis, and antibody responses in B cells, providing novel insight into post-transcriptional regulation and mitochondrial functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE275672 | GEO | 2024/08/31

REPOSITORIES: GEO

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RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response[RNA-seq]

Project description:B cells are crucial for adaptive immunity, orchestrating humoral responses by producing antibodies essential for pathogen clearance. Here, we show that Poly(rC) binding protein 1 (Pcbp1), a multifunctional RNA-binding protein, is a key regulator of antibody production in B cells. Pcbp1 deficiency in B cells resulted in significant reductions in IgM expression at steady state and compromised differentiation of germinal center B cells and production of high-affinity antibodies upon immunization. These effects result from compromised mitochondrial integrity in Pcbp1-deficient B cells, including compromised mitochondrial electron transport chain (ETC) complex I and increased mitochondrial ROS production. Blocking mitochondrial ROS production rescued IgM production and improved germinal center responses caused by Pcbp1 deficiency. Mechanistically, Pcbp1 promotes the expression of Fdxr, a critical component of ETC complex I, via binding to its 3’UTR. Overall, our findings reveal a novel role for Pcbp1 in regulating mitochondrial function, protein synthesis, and antibody responses in B cells, providing novel insight into post-transcriptional regulation and mitochondrial functions.

2024-08-31 | GSE275669 | 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.

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

Project description:Memory B cells (MBCs) play a critical role in protection against homologous and variant pathogen challenge by either differentiating to plasma cells (PCs) or to germinal center (GCs) B cells. The human MBC compartment contains both switched IgG+ and unswitched IgM+ MBCs and at present the contribution of these MBC subpopulations to protection is incompletely understood. We discovered that intrinsic antigen-affinity thresholds for activation were at least 100-fold higher for IgG+ as compared to IgM+ MBCs and that IgG+ MBCs when challenged responded only to high affinity antigens and differentiated almost exclusively towards PC fates. In contrast, IgM+ MBCs were eliminated by apoptosis by high affinity antigens and responded to low affinity antigens by differentiating towards GC B cell fates. Thus, IgG+ and IgM+ MBCs may play distinct yet complementary roles in response to pathogen challenge to ensure the immediate production of high affinity antibodies to homologous and closely related challenges and the generation of variant-specific MBCs through GC reactions.

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RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response[RNA-seq]

Project description:RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response[RNA-seq]

| PRJNA1152554 | ENA

RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response[scRNA-seq]

Project description:RNA binding protein Pcbp1 maintains mitochondria integrity to promote antibody production and germinal center response[scRNA-seq]

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Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation

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Expression Data from in vivo Tfh vs GC Tfh vs non-Tfh

Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation. Analysis of in vivo polyclonal GC Tfh vs Tfh vs Non-Tfh eight days after LCMV viral infection. Analysis of in vivo follicular helper CD4 T cells (CXCR5high GL7low), versus germinal center follicular helper CD4 T cells (CXCR5hi GL7hi), versus non-follicular helper CD4 T cells (CXCR5low) eight days after viral infection.

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2020-03-19 | GSE147182 | GEO

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2012-01-01 | E-GEOD-23169 | biostudies-arrayexpress

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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.

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