TSC1 Promotes B Cell Maturation but Is Dispensable for Germinal Center Formation

AbstractBlocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. Rodent-infectious species of Plasmodium such as P. yoelii (Py) serve as key tools to study vaccine efficacy and disease biology in immune-competent experimental animals. Here we evaluated the differences in vaccine-elicited humoral immunity in two widely used, and vastly diverged, inbred mouse strains, BALB/cJ and C57BL/6J, and identified immunological factors associated with protection. We vaccinated with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated protective efficacy after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice, whereas; all C57BL/6J mice were infected similar to controls. Interestingly, protection was mediated by antibodies, and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer germinal center experienced, CSP-specific class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that BALB/cJ mice achieved higher levels of B cell maturation in response to vaccination with PyCSP, which likely enabled the development of protective antibody responses. Overall, our study indicates that germinal center activity and B cell maturation are key processes in the development of vaccine-elicited protective antibodies against CSP.

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Germinal Center B-Cell-Associated Nuclear Protein (GANP) Involved in RNA Metabolism for B Cell Maturation

Advances in Immunology ◽

10.1016/bs.ai.2016.02.003 ◽

2016 ◽

pp. 135-186 ◽

Cited By ~ 4

Author(s):

N. Sakaguchi ◽

K. Maeda

Keyword(s):

B Cell ◽

Germinal Center ◽

Nuclear Protein ◽

Rna Metabolism ◽

Cell Maturation ◽

B Cell Maturation ◽

Germinal Center B Cell

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Expression of interleukin-9 receptor alpha on germinal center B cells: Potential role for interleukin-9 in B cell maturation

Journal of Allergy and Clinical Immunology ◽

10.1016/s0091-6749(02)82245-x ◽

2002 ◽

Vol 109 (1) ◽

pp. S356-S357

Author(s):

Lama Fawaz ◽

Abdelilah Soussi-Gounni ◽

Qutayba A Hamid ◽

Bruce D Mazer

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Potential Role ◽

Cell Maturation ◽

Receptor Alpha ◽

B Cell Maturation ◽

Interleukin 9 ◽

Germinal Center B Cells

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Single-cell analysis of human B cell maturation predicts how antibody class switching shapes selection dynamics

Science Immunology ◽

10.1126/sciimmunol.abe6291 ◽

2021 ◽

Vol 6 (56) ◽

pp. eabe6291 ◽

Cited By ~ 6

Author(s):

Hamish W. King ◽

Nara Orban ◽

John C. Riches ◽

Andrew J. Clear ◽

Gary Warnes ◽

...

Keyword(s):

Gene Expression ◽

B Cells ◽

B Cell ◽

Single Cell ◽

Germinal Center ◽

Cell Maturation ◽

B Cell Maturation ◽

Antibody Repertoires ◽

Antibody Class ◽

Human B Cell

Protective humoral memory forms in secondary lymphoid organs where B cells undergo affinity maturation and differentiation into memory or plasma cells. Here, we provide a comprehensive roadmap of human B cell maturation with single-cell transcriptomics matched with bulk and single-cell antibody repertoires to define gene expression, antibody repertoires, and clonal sharing of B cell states at single-cell resolution, including memory B cell heterogeneity that reflects diverse functional and signaling states. We reconstruct gene expression dynamics during B cell activation to reveal a pre–germinal center state primed to undergo class switch recombination and dissect how antibody class–dependent gene expression in germinal center and memory B cells is linked with a distinct transcriptional wiring with potential to influence their fate and function. Our analyses reveal the dynamic cellular states that shape human B cell–mediated immunity and highlight how antibody isotype may play a role during their antibody-based selection.

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Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation

JCI Insight ◽

10.1172/jci.insight.136653 ◽

2020 ◽

Vol 5 (10) ◽

Cited By ~ 6

Author(s):

Hannah G. Kelly ◽

Hyon-Xhi Tan ◽

Jennifer A. Juno ◽

Robyn Esterbauer ◽

Yi Ju ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Cell Maturation ◽

Memory B Cell ◽

Self Assembling ◽

B Cell Maturation ◽

Center Activity

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Dissection of the Pre-Germinal Center B-Cell Maturation Pathway in Common Variable Immunodeficiency Based on Standardized Flow Cytometric EuroFlow Tools

Frontiers in Immunology ◽

10.3389/fimmu.2020.603972 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lucía del Pino-Molina ◽

Eduardo López-Granados ◽

Quentin Lecrevisse ◽

Juan Torres Canizales ◽

Martín Pérez-Andrés ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Common Variable Immunodeficiency ◽

Germinal Center ◽

Normal Values ◽

Cell Maturation ◽

B Cell Maturation ◽

Immature B Cells ◽

The Impact ◽

Common Variable

IntroductionCommon Variable Immunodeficiency (CVID) is characterized by defective antibody production and hypogammaglobulinemia. Flow cytometry immunophenotyping of blood lymphocytes has become of great relevance for the diagnosis and classification of CVID, due to an impaired differentiation of mature post-germinal-center (GC) class-switched memory B-cells (MBC) and severely decreased plasmablast/plasma cell (Pb) counts. Here, we investigated in detail the pre-GC B-cell maturation compartment in blood of CVID patients.MethodsIn this collaborative multicentric study the EuroFlow PID 8-color Pre-GC B-cell tube, standardized sample preparation procedures (SOPs) and innovative data analysis tools, were used to characterize the maturation profile of pre-GC B-cells in 100 CVID patients, vs 62 age-matched healthy donors (HD).ResultsThe Pre-GC B-cell tube allowed identification within pre-GC B-cells of three subsets of maturation associated immature B-cells and three subpopulations of mature naïve B-lymphocytes. CVID patients showed overall reduced median absolute counts (vs HD) of the two more advanced stages of maturation of both CD5+ CD38+/++ CD21het CD24++ (2.7 vs 5.6 cells/µl, p=0.0004) and CD5+ CD38het CD21+ CD24+ (6.5 vs 17 cells/µl, p<0.0001) immature B cells (below normal HD levels in 22% and 37% of CVID patients). This was associated with an expansion of CD21-CD24- (6.1 vs 0.74 cells/µl, p<0.0001) and CD21-CD24++ (1.8 vs 0.4 cells/µl, p<0.0001) naïve B-cell counts above normal values in 73% and 94% cases, respectively. Additionally, reduced IgMD+ (21 vs 32 cells/µl, p=0.03) and IgMD- (4 vs 35 cells/µl, p<0.0001) MBC counts were found to be below normal values in 25% and 77% of CVID patients, respectively, always together with severely reduced/undetectable circulating blood pb. Comparison of the maturation pathway profile of pre-GC B cells in blood of CVID patients vs HD using EuroFlow software tools showed systematically altered patterns in CVID. These consisted of: i) a normally-appearing maturation pathway with altered levels of expression of >1 (CD38, CD5, CD19, CD21, CD24, and/or smIgM) phenotypic marker (57/88 patients; 65%) for a total of 3 distinct CVID patient profiles (group 1: 42/88 patients, 48%; group 2: 8/88, 9%; and group 3: 7/88, 8%) and ii) CVID patients with a clearly altered pre-GC B cell maturation pathway in blood (group 4: 31/88 cases, 35%).ConclusionOur results show that maturation of pre-GC B-cells in blood of CVID is systematically altered with up to four distinctly altered maturation profiles. Further studies, are necessary to better understand the impact of such alterations on the post-GC defects and the clinical heterogeneity of CVID.

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