G‐protein coupled receptors and ligands that organize humoral immune responses

Lu, Erick; Cyster, Jason G.

doi:10.1111/imr.12743

Cited by 61 publications

(74 citation statements)

References 148 publications

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“…Efficient humoral responses require B cells to integrate signals that coordinate their positioning, differentiation, and metabolic reprogramming (1)(2)(3). Productive interactions between B cells and T cells are central to these responses, as T cells provide key signals, such as CD40L and IL-21, that instruct B cell fate decisions and promote the formation of germinal centers (GCs) (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Productive interactions between B cells and T cells are central to these responses, as T cells provide key signals, such as CD40L and IL-21, that instruct B cell fate decisions and promote the formation of germinal centers (GCs) (3)(4)(5). GCs are transient anatomical structures that serve as the major sites of clonal expansion, affinity maturation, and plasma cell (PC) differentiation (1)(2)(3). The mature GC is histologically characterized by the appearance of 2 polarized microenvironments that facilitate the compartmentalization of specific functional processes (3).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to interactions with T cells, GC B cells respond to microenvironmental cues that regulate key GC processes and reinforce the transcriptional networks driving B cell differentiation (2). B cell positioning within the GC is controlled by several GPCRs and their chemokine and lipid ligands, including CXCL13, CXCL12, S1P, 7α,25-HC, and S-geranylgeranyl-l-glutathione (2,(14)(15)(16)(17). Disruption of these signaling pathways results in abnormal GC architecture, impaired B cell differentiation, and attenuated humoral responses (2).…”

Section: Introductionmentioning

confidence: 99%

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Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis

Ricker¹,

Chinenov²,

Pannellini³

et al. 2020

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis

Ricker¹,

Chinenov²,

Pannellini³

et al. 2020

Journal of Clinical Investigation

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“…Multiple genes associated with B cell activation and migration, such as Ackr2, Ackr4, GCsam, S1pr2 and Tnfrsf17, were upregulated in B cells from Cd23 cre/+ upon activation, compared to naïve B cells, but were not expressed in either DOT1L-deficient subsets (Figures 4E). Chemokine receptors expressed on B cells regulate their ability to migrate in response to chemokine gradients present in the microenvironment (Lu and Cyster, 2019). The atypical chemokine receptors Ackr2 and Ackr4 has been linked to regulation of B cell migration (Hansell et al, 2011;Kara et al, 2018).…”

Section: Downregulation Of Aicda In Dot1l-deficient Activated B Cellsmentioning

confidence: 99%

“…Together, these data revealed In particular, our study links histone modification to the regulation of a network of migrationrelated to genes and ultimately, B cell positioning in the follicle. Chemokine receptors expressed on B cells regulate their ability to migrate in response to chemokine gradients present in the microenvironment (Lu and Cyster, 2019). Amongst the molecules identified by transcriptomic analyses were S1pr2, as well as the atypical chemokine receptors Ackr2 and Ackr4.…”

Section: Dot1l Regulates Localization Of Activated B Cells During a Hmentioning

confidence: 99%

The histone methyltransferase DOT1L is essential for humoral immune responses

Kealy

Pietro

Scheer

et al. 2019

Preprint

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Short running title: B cell responses require DOT1L. Abbreviations used: AID -activation-induced cytidine deaminase; ASCs -antibody-secreting cells; BCL6 -B cell lymphoma-6; CPM -counts per million; CTV -cell trace violet; DOT1Ldisruptor of telomeric silencing 1-like, EZH2 -enhancer of zeste homolog 2; FVS -fixable viability stain; H3K27me3 -trimethylation of lysine 27 on histone H3; Ig -immunoglobulin; KLH -Keyhole Limpet Hemocyanin; MLLr-ALL -Mixed Lineage Leukaemia-rearranged acute lymphoblastic leukaemia; NP -(4-Hydroxy-3-nitrophenyl)-acetyl; PRC2 -polycomb repressive complex 2; S1PR -sphingosine-1-phosphate receptor; Th cells -T helper cells. ABSTRACT Histone modifiers are essential molecular regulators that underpin the ability of immune cells to reprogram their gene expression during differentiation. The recruitment of the histone methyltransferase DOT1L induces oncogenic gene expression in a subset of B cell leukemia. Despite its importance, little is known about its role in the humoral immune system. Herein, we demonstrate that DOT1L is a critical regulator of B cell biology. Dot1l f/f Mb1 Cre/+ mice had a block in B cell development, culminating in a significant reduction of mature B cells in the periphery. Upon immunization or influenza infection, germinal centers failed to form in Dot1l f/f Cd23 Cre/+ mice. Consequently, immunized mice revealed that DOT1L was essential for the formation of B cell memory populations. Dot1l deletion significantly attenuated the formation of class-switched antibody-secreting cells in both T-dependent and T-independent responses. Transcriptome, pathway and histological analysis identified a key role for DOT1L in reprogramming gene expression for migration and localization during the initial stages of a humoral response. Together, these results demonstrate an essential role for DOT1L in antigen-dependent B cell differentiation and hence, in generating an effective and lasting humoral immune response.

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Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis

et al. 2023

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The sustained immunosuppression associated with severe sepsis favors an increased susceptibility to secondary infections and remains incompletely understood. Plasmablast and plasma cell subsets, whose primary function is to secrete antibodies, have emerged as important suppressive populations that expand during sepsis. In particular, sepsis supports CD39hi plasmablast metabolic reprogramming associated with adenosine‐mediated suppressive activity. Arginine deficiency has been linked to an increased risk of secondary infections in sepsis. Overcoming arginine shortage by citrulline administration efficiently improves sepsis‐induced immunosuppression and secondary infections in the cecal ligation and puncture murine model. Here, we aimed to determine the impact of citrulline administration on B cell suppressive responses in sepsis. We demonstrate that restoring arginine bioavailability through citrulline administration markedly reduces the dominant extrafollicular B cell response, decreasing the immunosuppressive LAG3+ and CD39+ plasma cell populations, and restoring splenic follicles. At the molecular level, the IRF4/MYC‐mediated B cell reprogramming required for extrafollicular plasma cell differentiation is shunted in the splenic B cells of mice fed with citrulline. Our study reveals a prominent impact of nutrition on B cell responses and plasma cell differentiation and further supports the development of citrulline‐based clinical studies to prevent sepsis‐associated immune dysfunction.

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G‐protein coupled receptors and ligands that organize humoral immune responses

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 61 publications

References 148 publications

Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis

Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis

The histone methyltransferase DOT1L is essential for humoral immune responses

Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis

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