Bridging the B Cell Gap: Novel Technologies to Study Antigen-Specific Human B Cell Responses

The generation of high affinity antibodies is a crucial aspect of immunity induced by vaccination or infection. Investigation into the B cells that produce these antibodies grants key insights into the effectiveness of novel immunogens to induce a lasting protective response against endemic or pandemic pathogens, such as influenza viruses, human immunodeficiency virus, or severe acute respiratory syndrome coronavirus-2. However, humoral immunity has largely been studied at the serological level, limiting our knowledge on the specificity and function of B cells recruited to respond to pathogens. In this review, we cover a number of recent innovations in the field that have increased our ability to connect B cell function to the B cell repertoire and antigen specificity. Moreover, we will highlight recent advances in the development of both ex vivo and in vivo models to study human B cell responses. Together, the technologies highlighted in this review can be used to help design and validate new vaccine designs and platforms.

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B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-204049 ◽

2013 ◽

Vol 74 (1) ◽

pp. 294-302 ◽

Cited By ~ 22

Author(s):

Laetitia Rapetti ◽

Konstantia-Maria Chavele ◽

Catherine M Evans ◽

Michael R Ehrenstein

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

B Cell ◽

Mononuclear Cells ◽

Cell Function ◽

Cell Resistance ◽

Cell Responses ◽

B Cell Responses

ObjectiveTo investigate whether regulatory T cells (Treg) can control B cell function in rheumatoid arthritis (RA) and if not to explore the basis for this defect.MethodsSuppression of B cell responses by Treg was analysed in vitro by flow cytometry and ELISA using peripheral blood mononuclear cells from 65 patients with RA and 41 sex-matched and aged-matched healthy volunteers. Blocking and agonistic antibodies were used to define the role of Fas-mediated apoptosis in B cell regulation.ResultsTreg failed to restrain B cell activation, proinflammatory cytokine and antibody production in the presence of responder T cells in RA patients. This lack of suppression was not only caused by impaired Treg function but was also due to B cell resistance to regulation. In healthy donors, control by Treg was associated with increased B cell death and relied upon Fas-mediated apoptosis. In contrast, RA B cells had reduced Fas expression compared with their healthy counterparts and were resistant to Fas-mediated apoptosis.ConclusionsThese studies demonstrate that Treg are unable to limit B cell responses in RA. This appears to be primarily due to B cell resistance to suppression, but Treg defects also contribute to this failure of regulation. Our data identify the Fas pathway as a novel target for Treg-mediated suppression of B cells and highlight a potential therapeutic approach to restore control of B cells by Treg in RA patients.

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TLR-9 agonist and CD40-targeting vaccination induces HIV-1 envelope-specific B cells with a diversified immunoglobulin repertoire in humanized mice

PLoS Pathogens ◽

10.1371/journal.ppat.1009025 ◽

2020 ◽

Vol 16 (11) ◽

pp. e1009025

Author(s):

Véronique Godot ◽

Colas Tcherakian ◽

Laurine Gil ◽

Iñaki Cervera-Marzal ◽

Guangming Li ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Humanized Mice ◽

Hematopoietic Stem ◽

Cell Responses ◽

Clade C ◽

Specific Igg ◽

B Cell Responses ◽

Hiv 1 ◽

Human B Cell

The development of HIV-1 vaccines is challenged by the lack of relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with human hematopoietic stem cells (hu-mice), human B cell-development and function are impaired and cells fail to efficiently transition from IgM B cells to IgG B cells. Here, we found that CD40-targeted vaccination combined with CpG-B adjuvant overcomes the usual defect of human B-cell switch and maturation in hu-mice. We further dissected hu-B cell responses directed against the HIV-1 Env protein elicited by targeting Env gp140 clade C to the CD40 receptor of antigen-presenting cells. The anti-CD40.Env gp140 vaccine was injected with CpG-B in a homologous prime/boost regimen or as a boost of a NYVAC-KC pox vector encoding Env gp140 clade C. Both regimens elicited Env-specific IgG-switched memory hu-B cells at a greater magnitude in hu-mice primed with NYVAC-KC. Single-cell RNA-seq analysis showed gp140-specific hu-B cells to express polyclonal IgG1 and IgG3 isotypes and a broad Ig VH/VL repertoire, with predominant VH3 family gene usage. These cells exhibited a higher rate of somatic hypermutation than the non-specific IgG+ hu-B-cell counterpart. Both vaccine regimens induced splenic GC-like structures containing hu-B and hu-Tfh-like cells expressing PD-1 and BCL-6. We confirmed in this model that circulating ICOS+ memory hu-Tfh cells correlated with the magnitude of gp140-specific B-cell responses. Finally, the NYVAC-KC heterologous prime led to a more diverse clonal expansion of specific hu-B cells. Thus, this study shows that CD40-targeted vaccination induces human IgG production in hu-mice and provides insights for the development of a CD40-targeting vaccine to prevent HIV-1 infection in humans.

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Mast Cell Modulation of B Cell Responses: An Under-Appreciated Partnership in Host Defence

Frontiers in Immunology ◽

10.3389/fimmu.2021.718499 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alejandro M. Palma ◽

Mark R. Hanes ◽

Jean S. Marshall

Keyword(s):

B Cells ◽

Mast Cells ◽

B Cell ◽

Cell Function ◽

Surface Receptors ◽

Cell Responses ◽

Class Switch ◽

Mucosal Surfaces ◽

B Cell Responses

Mast cells are well known to be activated via cross-linking of immunoglobulins bound to surface receptors. They are also recognized as key initiators and regulators of both innate and adaptive immune responses against pathogens, especially in the skin and mucosal surfaces. Substantial attention has been given to the role of mast cells in regulating T cell function either directly or indirectly through actions on dendritic cells. In contrast, the ability of mast cells to modify B cell responses has been less explored. Several lines of evidence suggest that mast cells can greatly modify B cell generation and activities. Mast cells co-localise with B cells in many tissue settings and produce substantial amounts of cytokines, such as IL-6, with profound impacts on B cell development, class-switch recombination events, and subsequent antibody production. Mast cells have also been suggested to modulate the development and functions of regulatory B cells. In this review, we discuss the critical impacts of mast cells on B cells using information from both clinical and laboratory studies and consider the implications of these findings on the host response to infections.

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