The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells

Roy, Koushik; Chakraborty, Mainak; Kumar, Ashok; Manna, Asit Kumar; Roy, Neeladri Sekhar

doi:10.3389/fimmu.2023.1185597

Cited by 2 publications

(2 citation statements)

References 170 publications

(323 reference statements)

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“…Stimulation of B cells activates both cRel and RelA, which typically bind to the same kB motifs in most target gene promoters ( 42 , 43 ). We leveraged the dual reporter to show that cRel and RelA abundances are highly correlated in B cells.…”

Section: Discussionmentioning

confidence: 99%

Direct observation correlates NFκB cRel in B cells with activating and terminating their proliferative program

Vaidehi Narayanan,

Xiang,

Chen

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Antibody responses require the proliferative expansion of B cells controlled by affinity-dependent signals. Yet, proliferative bursts are heterogeneous, varying between 0 and 8 divisions in response to the same stimulus. NFκB cRel is activated in response to immune stimulation in B cells and is genetically required for proliferation. Here, we asked whether proliferative heterogeneity is controlled by natural variations in cRel abundance. We developed a fluorescent reporter mTFP1-cRel for the direct observation of cRel in live proliferating B cells. We found that cRel is heterogeneously distributed among naïve B cells, which are enriched for high expressors in a heavy-tailed distribution. We found that high cRel expressors show faster activation of the proliferative program, but do not sustain it well, with population expansion decaying earlier. With a mathematical model of the molecular network, we showed that cRel heterogeneity arises from balancing positive feedback by autoregulation and negative feedback by its inhibitor IκBε, confirmed by mouse knockouts. Using live-cell fluorescence microscopy, we showed that increased cRel primes B cells for early proliferation via higher basal expression of the cell cycle driver cMyc. However, peak cMyc induction amplitude is constrained by incoherent feedforward regulation, decoding the fold change of cRel activity to terminate the proliferative burst. This results in a complex nonlinear, nonmonotonic relationship between cRel expression and the extent of proliferation. These findings emphasize the importance of direct observational studies to complement gene knockout results and to learn about quantitative relationships between biological processes and their key regulators in the context of natural variations.

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Section: Discussionmentioning

confidence: 99%

Direct observation correlates NFκB cRel in B cells with activating and terminating their proliferative program

Vaidehi Narayanan,

Xiang,

Chen

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…B cells recognize antigens through B-cell antigen receptors, whereas APCs recognize antigens through uptake, then present antigens to Th cells in the form of MHC-II-antigen complexes. The activated Th2 cells produce multiple cytokines, such as IL-4, IL-5, and IL-10, which can provide synergistic stimulatory signals to B cells. – After being stimulated by these, B cells begin a series of proliferation and differentiation. Most of them differentiate into plasma cells and produce antibodies.…”

Section: Mechanisms Of Tumor Vaccinesmentioning

confidence: 99%

Components, Formulations, Deliveries, and Combinations of Tumor Vaccines

Liu,

Yao,

Sun

et al. 2024

ACS Nano

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Tumor vaccines, an important part of immunotherapy, prevent cancer or kill existing tumor cells by activating or restoring the body's own immune system. Currently, various formulations of tumor vaccines have been developed, including cell vaccines, tumor cell membrane vaccines, tumor DNA vaccines, tumor mRNA vaccines, tumor polypeptide vaccines, virus-vectored tumor vaccines, and tumor-in-situ vaccines. There are also multiple delivery systems for tumor vaccines, such as liposomes, cell membrane vesicles, viruses, exosomes, and emulsions. In addition, to decrease the risk of tumor immune escape and immune tolerance that may exist with a single tumor vaccine, combination therapy of tumor vaccines with radiotherapy, chemotherapy, immune checkpoint inhibitors, cytokines, CAR-T therapy, or photoimmunotherapy is an effective strategy. Given the critical role of tumor vaccines in immunotherapy, here, we look back to the history of tumor vaccines, and we discuss the antigens, adjuvants, formulations, delivery systems, mechanisms, combination therapy, and future directions of tumor vaccines.

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The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells

Cited by 2 publications

References 170 publications

Direct observation correlates NFκB cRel in B cells with activating and terminating their proliferative program

Direct observation correlates NFκB cRel in B cells with activating and terminating their proliferative program

Components, Formulations, Deliveries, and Combinations of Tumor Vaccines

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