The expansion of human T-bet
            <sup>high</sup>
            CD21
            <sup>low</sup>
            B cells is T cell dependent

Keller, Baerbel; Strohmeier, Valentina; Harder, Ina; Unger, Susanne; Payne, Kathryn; Andrieux, Geoffroy; Boerries, Melanie; Felixberger, Peter Tobias; Landry, Jonathan; Nieters, Alexandra; Rensing‐Ehl, Anne; Salzer, Ulrich; Frede, Natalie; Usadel, Susanne; Elling, Roland; Speckmann, Carsten; Hainmann, Ina; Ralph, Elizabeth; Gilmour, Kimberly; Wentink, Marjolein; Burg, Mirjam van der; Kuehn, Hye Sun; Rosenzweig, Sergio D.; Kölsch, Uwe; Bernuth, Horst von; Kaiser-Labusch, Petra; Gothe, Florian; Hambleton, Sophie; Vlagea, Alexandru; García, Ana García; Alsina, Laia; Markelj, Gašper; Avčin, Tadej; Vasconcelos, Júlia; Guedes, Margarida; Ding, Jing-Ya; Ku, Cheng‐Lung; Shadur, Bella; Avery, Danielle T.; Venhoff, Nils; Thiel, Jens; Becker, Heiko; Erazo-Borrás, Lucía Victoria; Trujillo-Vargas, Claudia M.; Franco, José Luis; Fieschi, Claire; Okada, Satoshi; Gray, Paul; Uzel, Gülbû; Casanova, Jean‐Laurent; Fliegauf, Manfred; Grimbacher, Bodo; Eibel, Hermann; Ehl, Stephan; Voll, Reinhard; Rizzi, Marta; Stepensky, Polina; Beneš, Vladimı́r; Cindy, S.; Bossen, Claudia; Tangye, Stuart G.; Warnatz, Klaus

doi:10.1126/sciimmunol.abh0891

Cited by 109 publications

(65 citation statements)

References 71 publications

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“…Cell isolation: PBMCs were isolated from EDTA blood by Ficoll density centrifugation following standard protocols. Given the concordance of CD21 low CD38 low B cells and T-bet high CD21 low B cells [17] in the following, T-bet high CD21 low B cells were defined by CD21 low CD38 neg and referred to as CD21 low B cells. Naïve B cells were isolated using the naïve B cell isolation kit (Miltenyi Biotech, Bergisch Gladbach, Germany) following the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…RNAseq: RNA of 50,000-275,000 sorted naïve CD21 pos B cells from CVID patients and HD and patient-derived CD21 low B cells were isolated and processed for RNAseq as described before [17]. An amount of 10 ng of RNA (RIN as determined by Bioanalyzer; Agilent Technologies, Franfurt, Germany: 7.9-9.9) was loaded.…”

Section: Methodsmentioning

confidence: 99%

“…To ensure optimal comparability of patient and HD-derived B cells, analysis was restricted to the IgM pos CD27 neg naïve B-cell compartment, and in the following CD21 low and CD21 pos B cells refer to the respective naïve B-cell subsets (Figure 1A and see Supplementary Figure S1A for the full gating strategy). Given the low proportions of CD21 low B cells in most healthy individuals, this population was not further investigated in HD [17]. patients and HD (Figure 2D).…”

Section: Akt Mtor and S6 Phosphorylation In B-cell Subpopulations Of Cvid Patientsmentioning

confidence: 99%

“…T-bet high CD21 low B cells typically accumulate in the context of chronic immune activation in CVID, autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), chronic infections by HIV, HCV or Plasmodium falciparum and others [8][9][10][11][12][13]. The expansion of this B-cell population depends on antigen-induced B-cell receptor (BCR)-as well as T-cell-derived IFNγ-, CD40-and IL-21-signals resulting in a unique transcriptional profile including high levels of the transcription factor T-bet [14][15][16][17][18][19]. We and others have reported disturbed BCR signaling at the level of SYK, BLNK, PLCγ2, reduced Ca 2+ mobilization and NF-κB activation in CD21 low B cells and homologous populations in different disease conditions [10,[20][21][22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

“…Gain of function mutations (GOF) in PIK3CD encoding p110δ (APDS1) or loss of function (LOF) mutations in PIK3R1 encoding p85α (APDS2) are associated with increased phosphorylation of AKT and subsequent targets as the ribosomal subunit S6 in lymphocytes [34,38]. Increased proportions of transitional B cells and T-bet high CD21 low B cells and a loss of class-switched memory B cells have been described [17,36,37,39,40]. Thus, some APDS patients present clinically and immunologically in a similar way as CVID.…”

Section: Introductionmentioning

confidence: 99%

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Dysregulated PI3K Signaling in B Cells of CVID Patients

Harder

Münchhalfen

Andrieux

et al. 2022

Cells

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The altered wiring of signaling pathways downstream of antigen receptors of T and B cells contributes to the dysregulation of the adaptive immune system, potentially causing immunodeficiency and autoimmunity. In humans, the investigation of such complex systems benefits from nature’s experiments in patients with genetically defined primary immunodeficiencies. Disturbed B-cell receptor (BCR) signaling in a subgroup of common variable immunodeficiency (CVID) patients with immune dysregulation and expanded T-bethighCD21low B cells in peripheral blood has been previously reported. Here, we investigate PI3K signaling and its targets as crucial regulators of survival, proliferation and metabolism by intracellular flow cytometry, imaging flow cytometry and RNAseq. We observed increased basal but disturbed BCR-induced PI3K signaling, especially in T-bethighCD21low B cells from CVID patients, translating into impaired activation of crucial downstream molecules and affecting proliferation, survival and the metabolic profile. In contrast to CVID, increased basal activity of PI3K in patients with a gain-of-function mutation in PIK3CD and activated PI3K delta syndrome (APDS) did not result in impaired BCR-induced AKT-mTOR-S6 phosphorylation, highlighting that signaling defects in B cells in CVID and APDS patients are fundamentally different and that assessing responses to BCR stimulation is an appropriate confirmative diagnostic test for APDS. The active PI3K signaling in vivo may render autoreactive T-bethighCD21low B cells in CVID at the same time to be more sensitive to mTOR or PI3K inhibition.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Akt Mtor and S6 Phosphorylation In B-cell Subpopulations Of Cvid Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dysregulated PI3K Signaling in B Cells of CVID Patients

Harder

Münchhalfen

Andrieux

et al. 2022

Cells

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Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers

Gofshteyn

Mansfield

Spitznagle

et al. 2023

Arthritis & Rheumatology

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Objective. This study was undertaken to identify blood markers of juvenile dermatomyositis (DM) disease activity (DA), which are needed to improve disease management.Methods. The study comprised a total of 123 juvenile DM patients and 53 healthy controls. Results of laboratory tests (aldolase, creatinine kinase, lactate dehydrogenase [LDH], aspartate aminotransferase) and clinical measures of DA in patients with juvenile DM, including the Manual Muscle Testing in 8 muscles (MMT-8), Childhood Myositis Assessment Scale (CMAS), and disease activity scores (DAS) (total DAS for juvenile DM, the muscle DAS, and the skin DAS), were recorded when available. Surface phenotype of peripheral blood mononuclear cells was assessed using flow cytometry. Whole blood transcriptional profiles were studied using either RNA-sequencing or microarrays. Differential gene expression was determined using DESeq and compared by pathway and gene ontology analyses.Results. Conventional memory (CD27+IgD-) B cells expressing low CXCR5 levels (CXCR5 low/-CM B cells) were significantly increased in frequency and absolute numbers in 2 independent cohorts of juvenile DM patients compared with healthy controls. The frequency of CD4+ Th2 memory cells (CD45RA-CXCR5-CCR6-CXCR3-) was also increased in juvenile DM, especially in patients who were within <1 year from diagnosis. The frequency of CXCR5 low/-CM B cells correlated with serum aldolase levels and with a blood interferon-stimulated gene transcriptional signature. Furthermore, both the frequency and absolute numbers of CXCR5 low/-CM B cells correlated with clinical and laboratory measures of muscle DA (MMT-8, CMAS, aldolase, and LDH).Conclusion. These findings suggest that both CM B cells lacking the CXCR5 follicular marker and CXCR5-Th2 cells represent potential biomarkers of DA in juvenile DM and may contribute to its pathogenesis.

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Correlation of Professional Antigen‐Presenting Tbet⁺CD11c⁺ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis

McGrath,

Grimstad,

Thorarinsdottir

et al. 2024

Arthritis & Rheumatology

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ObjectiveSubsets of CD21–/low memory B cells (MBCs), including double‐negative (DN, CD27–IgD–) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21–/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21–/low Tbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in untreated RA patients (uRA).MethodsClinical observations were combined with flow cytometry (n=36) and single cell (sc)RNA and V(D)J sequencing (n=4) of peripheral blood MBCs from uRA patients. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA‐sequencing data of synovial B cells. In vitro co‐culture of Tbet+CD11c+ B cells with T cells was used to assess co‐stimulatory capacity.ResultsCD21–/low Tbet+CD11c+ MBCs in peripheral blood correlated with bone destruction but no other clinical parameters analysed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V‐genes. Gene expression analysis of these cells identified a unique signature of over 150 upregulated genes associated with antigen presentation functions including: BCR activation and clathrin‐mediated antigen internalisation, regulation of actin filaments, endosomes and lysosomes, antigen processing, loading, presentation and co‐stimulation, a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced RORγT expression in CD4+ T cells, thereby polarising to Th17 cells, a T‐cell subset critical for osteoclastogenesis and associated with bone destruction.ConclusionThis study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T‐cell activation and Th17 polarisation.image

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The expansion of human T-bet ^high CD21 ^low B cells is T cell dependent

Abstract: T cell–derived IFNγ and CD40L/IL-21R signals are crucial for the differentiation of human T-bet high CD21 low B cells.

Cited by 109 publications

References 71 publications

Dysregulated PI3K Signaling in B Cells of CVID Patients

Dysregulated PI3K Signaling in B Cells of CVID Patients

Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers

Correlation of Professional Antigen‐Presenting Tbet⁺CD11c⁺ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis

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The expansion of human T-bet high CD21 low B cells is T cell dependent

Abstract: T cell–derived IFNγ and CD40L/IL-21R signals are crucial for the differentiation of human T-bet high CD21 low B cells.

Cited by 109 publications

References 71 publications

Dysregulated PI3K Signaling in B Cells of CVID Patients

Dysregulated PI3K Signaling in B Cells of CVID Patients

Association of Juvenile Dermatomyositis Disease Activity With the Expansion of Blood Memory B and T Cell Subsets Lacking Follicular Markers

Correlation of Professional Antigen‐Presenting Tbet+CD11c+ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis

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Product

Resources

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The expansion of human T-bet ^high CD21 ^low B cells is T cell dependent

Correlation of Professional Antigen‐Presenting Tbet⁺CD11c⁺ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis