DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
In follicular lymphoma (FL), surface immunoglobulin (sIg) carries mandatory N-glycosylation sites in the variable regions, inserted during somatic hypermutation. These glycosylation sites are tumor-specific, indicating a critical function in FL. Added glycan unexpectedly terminates at high mannose (Mann) and confers capability for sIg-mediated interaction with local macrophage-expressed DC-SIGN lectin resulting in low-level activation of upstream B-cell receptor signaling responses. Here we show that despite being of low-level, DC-SIGN induces a similar downstream transcriptional response to anti-IgM in primary FL cells, characterized by activation of pathways associated with B-cell survival, proliferation and cell–cell communication. Lectin binding was also able to engage post-transcriptional receptor cross-talk pathways since, like anti-IgM, DC-SIGN down-modulated cell surface expression of CXCR4. Importantly, pre-exposure of a FL-derived cell line expressing sIgM-Mann or primary FL cells to DC-SIGN, which does not block anti-IgM binding, reversibly paralyzed the subsequent Ca2+ response to anti-IgM. These novel findings indicate that modulation of sIg function occurs in FL via lectin binding to acquired mannoses. The B-cell receptor alternative engagement described here provides two advantages to lymphoma cells: (i) activation of signaling, which, albeit of low-level, is sufficient to trigger canonical lymphoma-promoting responses, and (ii) protection from exogenous antigen by paralyzing anti-IgM-induced signaling. Blockade of this alternative engagement could offer a new therapeutic strategy.
Valle-Argos, Beatriz
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Chiodin, Giorgia
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Bryant, Dean
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Taylor, Joe
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Lemm, Elizabeth
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Duriez, Patrick
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Rock, Philip J
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Strefford, Jonathan
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Forconi, Francesco
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Burack, Richard
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Packham, Graham
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Stevenson, Freda
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3 June 2021
Valle-Argos, Beatriz
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Chiodin, Giorgia
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Bryant, Dean
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Taylor, Joe
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Lemm, Elizabeth
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Duriez, Patrick
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Rock, Philip J
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Strefford, Jonathan
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Forconi, Francesco
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Burack, Richard
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Packham, Graham
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Stevenson, Freda
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Valle-Argos, Beatriz, Chiodin, Giorgia, Bryant, Dean, Taylor, Joe, Lemm, Elizabeth, Duriez, Patrick, Rock, Philip J, Strefford, Jonathan, Forconi, Francesco, Burack, Richard, Packham, Graham and Stevenson, Freda
(2021)
DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity.
Scientific Reports, 11 (1), [11676].
(doi:10.1038/s41598-021-91112-7).
Abstract
In follicular lymphoma (FL), surface immunoglobulin (sIg) carries mandatory N-glycosylation sites in the variable regions, inserted during somatic hypermutation. These glycosylation sites are tumor-specific, indicating a critical function in FL. Added glycan unexpectedly terminates at high mannose (Mann) and confers capability for sIg-mediated interaction with local macrophage-expressed DC-SIGN lectin resulting in low-level activation of upstream B-cell receptor signaling responses. Here we show that despite being of low-level, DC-SIGN induces a similar downstream transcriptional response to anti-IgM in primary FL cells, characterized by activation of pathways associated with B-cell survival, proliferation and cell–cell communication. Lectin binding was also able to engage post-transcriptional receptor cross-talk pathways since, like anti-IgM, DC-SIGN down-modulated cell surface expression of CXCR4. Importantly, pre-exposure of a FL-derived cell line expressing sIgM-Mann or primary FL cells to DC-SIGN, which does not block anti-IgM binding, reversibly paralyzed the subsequent Ca2+ response to anti-IgM. These novel findings indicate that modulation of sIg function occurs in FL via lectin binding to acquired mannoses. The B-cell receptor alternative engagement described here provides two advantages to lymphoma cells: (i) activation of signaling, which, albeit of low-level, is sufficient to trigger canonical lymphoma-promoting responses, and (ii) protection from exogenous antigen by paralyzing anti-IgM-induced signaling. Blockade of this alternative engagement could offer a new therapeutic strategy.
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More information
Accepted/In Press date: 20 May 2021
Published date: 3 June 2021
Additional Information:
Funding Information:
The authors thank the patients involved in this study for the kind gift of samples and Dr. Kathy Potter (Tissue Bank, Cancer Sciences, University of Southampton) for processing and storage of FL samples. This work was supported by Grants from Cancer Research UK [C2750/A23669, C42023/A29370, C36811/A29101], the Southampton Experimental Cancer Medicine and Cancer Research Centers [C24563/A15581; C34999/A18087], Worldwide Cancer Research [13-0267] and Bloodwise [18009].
Funding Information:
J. Strefford reports receiving commercial research grants from Roche. F. Forconi reports receiving commercial research grants from Gilead sciences. B. Valle-Argos, G. Chiodin, D. J. Bryant, J. Taylor, E. Lemm, P. Duriez, P. J. Rock, R. W. Burack, G. Packham and F. K. Stevenson have no competing interests.
Publisher Copyright:
© 2021, The Author(s).
Identifiers
Local EPrints ID: 449811
URI: http://eprints.soton.ac.uk/id/eprint/449811
ISSN: 2045-2322
PURE UUID: 20417102-f7ac-41b7-8e3f-5669945f7313
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Date deposited: 18 Jun 2021 16:30
Last modified: 17 Mar 2024 03:35
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Contributors
Author:
Beatriz Valle-Argos
Author:
Giorgia Chiodin
Author:
Dean Bryant
Author:
Joe Taylor
Author:
Elizabeth Lemm
Author:
Patrick Duriez
Author:
Philip J Rock
Author:
Richard Burack
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