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Follicular dendritic cells restrict IL4 availability in germinal centers and foster memory B cell generation

ABSTRACT: Germinal centers (GCs) are sites of antibody affinity maturation and memory B cell generation. Follicular dendritic cells (FDCs) form a dense stromal network within GCs, but the full extent of their supportive activity is not understood. Here we showed that FDCs expressed IL4Ra and they reduced IL4 availability in GCs. We used scRNA-seq to examine IL4 actions within the GC and identified a subset of light zone cells marked by high IL4Ra and CD23 and lack of a Myc gene-expression signature. Trajectory inference analysis suggested this population could differentiate into pre-memory and pre-plasma cells. Genetic experiments showed that IL4Ra and STAT6 acted intrinsically to restrain pre-memory B cell generation. By reducing IL4 availability, FDCs enhanced GC B cell selection and fostered memory cell generation. This work suggests that GC FDCs provide a niche that limits bystander IL4 activity, focusing IL4 action on B cells undergoing selection and enhancing memory cell differentiation

ORGANISM(S): Mus musculus

PROVIDER: GSE180920 | GEO | 2021/09/15

REPOSITORIES: GEO

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Expression data from murine follicular dendritic cells

Project description:Germinal centers (GCs) are clusters of activated B cells built on stromal cells known as follicular dendritic cells (FDCs). In the Peyerâs patches (PPs), GCs are chronically induced by bacteria and are the major sites for generation of gut IgA immune responses. Whether FDCs directly contribute to the IgA production in PP GCs is unknown. To investigate the role FDCs in gut immune system, we examined comprehensive gene profiles of FDCs purified from PPs or perypheral lymph nodes (pLNs) with or without immunization. We also tried to reconstitute the PP FDC signature in vitro by pulsed or continuous stimulation of pLN FDCs through TLRs, RARs or simultaneously through TLRs and RARs. The number of samples is as follows; ex vivo naÃ¯ve pLN FDC=3, ex vivo immunized pLN FDC=2, ex vivo PP FDCs=3, in vitro without stimulation=2, in vitro with LPS stimulation for 5 hours=1, in vitro with LPS stimulation for 72h=1, in vitro with Pam2CSK4 (Pam) stimulation for 96h=2, in vitro with retinoic acid(RA) stimulation for 96h=2,in vitro with RA+Pam stimulation for 96h=2. In addition, ex vivo FDCs with or without immunizations were compared (3 samples), or in vitro cultured FDCs with or without various stimulations were compared (6 samples)

2010-07-30 | E-GEOD-19401 | biostudies-arrayexpress

Expression data from murine follicular dendritic cells

Project description:Germinal centers (GCs) are clusters of activated B cells built on stromal cells known as follicular dendritic cells (FDCs). In the Peyer’s patches (PPs), GCs are chronically induced by bacteria and are the major sites for generation of gut IgA immune responses. Whether FDCs directly contribute to the IgA production in PP GCs is unknown. To investigate the role FDCs in gut immune system, we examined comprehensive gene profiles of FDCs purified from PPs or perypheral lymph nodes (pLNs) with or without immunization. We also tried to reconstitute the PP FDC signature in vitro by pulsed or continuous stimulation of pLN FDCs through TLRs, RARs or simultaneously through TLRs and RARs.

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Follicular dendritic cells restrict IL4 availability in germinal centers and foster memory B cell generation

Project description:Follicular dendritic cells restrict IL4 availability in germinal centers and foster memory B cell generation

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Transcription profiling of mouse primary splenocytes enriched or depleted of follicular dendritic cells to study the events leading to maturation of follicular dendritic cells and lymphoid germinal centers.

Project description:Comparison of follicular dendritic cell-enriched versus -depleted splenocytes. Affinity maturation and Ab class switches occur in lymphoid germinal centers (GCs), in which differentiation and maintenance depend on lymphotoxin (LT) signaling and include differentiation of follicular dendritic cells (FDCs). The events leading to FDC and GC maturation are poorly defined. Using several approaches of functional genomics, we enumerated transcripts affected in mice by suppressing LT receptor (LTR) signaling and/or overrepresented in FDC-enriched GC isolates. Protein expression analysis of 3 of 12 genes both enriched in FDCs and down-regulated by LTR signaling suppression validated them as FDC markers. Functional analysis of one of these three, clusterin, suggests a role as an FDC-derived trophic factor for GC B cells. Hence, the set of genes presented in this study includes markers emanating from LTR signaling and transcripts relevant to GC and FDC function.

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Characterization of human FDCs reveals regulation of T cells and antigen presentation to B cells [Affymetrix]

Project description:Stromal-derived follicular dendritic cells (FDCs) are essential for germinal centers (GCs), the site where B cells maturate their antibodies. FDCs present native antigen to B cells and maintain a CXCL13 gradient to form the B cell follicle. Yet despite their essential role, the transcriptome of human FDCs remains undefined. Using single-cell RNA sequencing and microarray, we provided the transcriptome of these enigmatic cells as a comprehensive resource. Key genes were validated by flow cytometry and microscopy. Surprisingly, marginal reticular cells (MRCs) rather than FDCs expressed B cell activating factor (BAFF). Furthermore, we found that human FDCs expressed TLR4 and can alter antigen availability in response to pathogen-associated molecular patterns (PAMPs). High expression of PD-L1 and PD-L2 on FDCs activated PD1 on T cells. In addition, we found expression of genes related to T cell regulation, such as HLA-DR, CD40, and others. These data suggest intimate contact between human FDCs and T cells.

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Project description:The expression of the Nerve growth factor receptor (NGFR) was described in follicular dendritic cells (FDCs), the major lymphoid stromal cell (LSC) compartment regulating B-cell activation within germinal centers (GCs). However, the role of NGFR in humoral response is not well defined. In this work, we have studied the effect of Ngfr KO in LNs organization and function. Ngfr KO led to spontaneous GC formation and expansion of GC B-cell compartment that were related on Ngfr depletion in non-hematopoietic radioresistant compartment. In agreement, Ngfr KO mice showed alterations in LSC with an increased frequency of FDCs harboring an activated phenotype characterized by the overexpression of CD21/35, MAdCAM-1, and VCAM-1. Moreover, Ngfr KO mice showed GC ectopic location, loss of polarization, impaired high-affinity antibody production, and increased circulating autoantibodies. In addition, Ngfr KO/Bcl2 Tg mice displayed increased levels of autoantibodies, higher incidence of autoimmunity, and decreased overall survival. Our work shows that NGFR maintains GC structure and functionality being involved in the regulation of antibody production and immune tolerance.

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Germinal centers continually recruit naïve T cells that alter the balance between follicular T helper and follicular regulatory T cells.

Project description:Follicular helper T cells (T FH ) mediate B cell selection and clonal expansion in germinal centers (GCs), and follicular regulatory T cells (T FR ) prevent the emergence of self-reactive B cells and help to extinguish the reaction. Here we show that GC reactions continually recruit T cells from both the naïve conventional and naive thymic regulatory T cell (Treg) repertoires. In the early GC, newly recruited T cells develop into T FH , whereas cells entering during the contraction phase develop into T FR cells that contribute to GC dissolution. The T FR fate decision is associated with decreased antigen availability and is modulated by slow antigen delivery or mRNA vaccination. Thus, invasion of ongoing GCs by newly developing T FH and T FR from naïve conventional and Treg repertoires, helps remodel the GC based on antigen availability.

2023-08-19 | GSE240730 | GEO

Deciphering imprints of impaired memory B-cell maturation in germinal centers of patients with Common variable immunodeficiency

Project description:Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes and poor antigen specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC) derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modelling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregular shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection and class-switching, while in patient 3, high SHM, impaired antigen selection and class-switching with large single clones imply increased re-cycling of cells within the irregular shaped GCs. In lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells is a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flowcytometry and BCR repertoire analysis reveals essential steps during memory formation.

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Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia

Project description:Glucocorticoids (GCs) are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the glucocorticoid receptor (GR), a ligand induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, the pathways that affect their regulation, and how resistance arises are not well understood. Here we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation shRNA screen to identify GC-regulated “effector” genes that contribute to cell death as well as genes that affect the sensitivity of B-ALL cells to dex. This analysis reveals a pervasive role for GCs in suppression of B-cell development genes that is linked to therapeutic response. Inhibition of PI3Kδ, a lynchpin in the pre-B-cell receptor and IL7R signaling pathways critical to B-cell development, with CAL-101 (idelalisib), interrupts a double-negative feedback loop, enhancing GC-regulated transcription to synergistically kill even highly resistant B-ALL with diverse genetic backgrounds. This work not only identifies numerous opportunities for enhanced lymphoid-specific combination chemotherapy that have the potential to overcome treatment resistance, but is also a valuable resource for understanding GC biology and the mechanistic details of GR-regulated transcription. Please note that the cell lines and primary samples were processed and normalized separately.

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