Atypical chemokine receptor 4 shapes activated B cell fate

Kara, Elodie; Bastow, Cameron R.; McKenzie, Duncan R.; Gregor, Carly E.; Fenix, Kevin; Babb, Rachelle; Norton, Todd S.; Zotos, Dimitra; Rodda, Lauren B.; Hermes, Jana R.; Bourne, Katherine; Gilchrist, Derek S.; Nibbs, Robert J. B.; Alsharifi, Mohammed; Vinuesa, Carola G.; Tarlinton, David M.; Brink, Robert; Hill, Geoffrey R.; Cyster, Jason G.; Comerford, Iain; McColl, Shaun R.

doi:10.1084/jem.20171067

Cited by 27 publications

(40 citation statements)

References 47 publications

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“…Furthermore, S1PR2 (the G protein-coupled sphingosine-1-phosphate receptor encoded by S1pr2) is critical for B cell confinement in the GC (Green and Cyster, 2012). While we did not observe in increase in GCs observed in Ackr4-deficient (Kara et al, 2018) and S1PR2deficient (Green and Cyster, 2012) mice, we hypothesized that disruption of the expression of multiple genes associated with early activation and migratory events in DOT1L-deficient B cells may result in early defective humoral responses in vivo.…”

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

confidence: 61%

“…While the role of Ackr2 in GC responses has not yet been studied, Ackr4 has recently been identified as a negative regulator of B cell responses with enforced expression of Ackr4 reducing B cell migration towards CCL21, a CCR7 ligand (Kara et al, 2018). Correspondingly, DOT1Ldeficient cells, which had a reduction in Ackr4, had an increased ability to migrate to CCL21 ( Figure S3E).…”

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

confidence: 99%

“…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%

“…In particular, 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). The atypical chemokine receptors Ackr2 and Ackr4 has been linked to regulation of B cell migration (Hansell et al, 2011;Kara et al, 2018), and S1PR2 (the G protein-coupled sphingosine-1phosphate receptor encoded by S1pr2) is required for retaining GC B cells in the follicle. While the role of Ackr2 in GC responses has not yet been studied, Ackr4 has recently been identified as a negative regulator of B cell responses with enforced expression or Ackr4 reducing B cell migration towards CCL21, a CCR7 ligand (Kara et al, 2018).…”

Section: Dot1l Regulates Expression Of Genes Required For Effective Bmentioning

confidence: 99%

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

confidence: 61%

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

confidence: 99%

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

confidence: 99%

Section: Dot1l Regulates Expression Of Genes Required For Effective Bmentioning

confidence: 99%

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The histone methyltransferase DOT1L is essential for humoral immune responses

Kealy

Pietro

Scheer

et al. 2019

Preprint

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“…ACKRs are mainly limited to stromal cells, although Ackr1 is expressed by erythrocyte precursors (not shown in Fig. 3) [164] and the other ACKRs are transcribed in discrete subsets of B cells [99, 189,226]. Leukocyte activation can change cCKR expression profiles dramatically to couple changes in immunological function with switches in migratory potential.…”

Section: The Function Of the Chemokine Networkmentioning

confidence: 99%

A guide to chemokines and their receptors

2018

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The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein‐coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behavior, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many nonleukocytic cell types. Chemokines are profoundly affected by post‐translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical ‘atypical’ chemokine receptors that regulate chemokine localization and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarizes the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focusing particularly on their ability to direct leukocyte migration.

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Atypical chemokine receptor 4 (ACKR4/CCX‐CKR): A comprehensive exploration across physiological and pathological landscapes in contemporary research

Naser,

Hamza,

Alhili

et al. 2024

Cell Biochemistry & Function

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Atypical chemokine receptor 4 (ACKR4), also known as CCX‐CKR, is a member of the chemokine receptor family that lacks typical G protein signaling activity. Instead, ACKR4 functions as a scavenger receptor that can bind and internalize a wide range of chemokines, influencing their availability and activity in the body. ACKR4 is involved in various physiological processes, such as immune cell trafficking and the development of thymus, spleen, and lymph nodes. Moreover, ACKR4 has been implicated in several pathological conditions, including cancer, heart and lung diseases. In cancer, ACKR4 plays a complex role, acting as a tumor suppressor or promoter depending on the type of cancer and the stage of the disease. For instance, ACKR4 may inhibit the growth and metastasis of breast cancer, but it may also promote the progression of hepatocellular carcinoma and gastric cancer. In inflammatory situations, ACKR4 has been found to modulate the recruitment and activation of immune cells, contributing to the pathogenesis of diseases such as myocardial infraction and pulmonary sarcoidosis. The study of ACKR4 is still ongoing, and further research is needed to fully understand its role in different physiological and pathological contexts. Nonetheless, ACKR4 represents a promising target for the development of novel therapeutic strategies for various diseases.

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Atypical chemokine receptor 4 shapes activated B cell fate

Abstract: Kara et al. show that ACKR4 regulates early activated B cell differentiation fate. ACKR4 limits the early proliferation of activated B cells by restricting their initial access to the splenic interfollicular zone.

Cited by 27 publications

References 47 publications

The histone methyltransferase DOT1L is essential for humoral immune responses

The histone methyltransferase DOT1L is essential for humoral immune responses

A guide to chemokines and their receptors

Atypical chemokine receptor 4 (ACKR4/CCX‐CKR): A comprehensive exploration across physiological and pathological landscapes in contemporary research

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