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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
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.
2045-2322
Valle-Argos, Beatriz
4fddaa71-c0aa-4b95-b464-8bdb592428a2
Chiodin, Giorgia
4b3e9525-b377-4d16-b69a-e05d2e7854fe
Bryant, Dean
10ed83e8-8080-4d9c-bba5-df9d4eec3a10
Taylor, Joe
6a4a31d0-defc-4b85-b4bd-1292b356ef51
Lemm, Elizabeth
f363493b-47ce-4f8e-9e94-272486397cb3
Duriez, Patrick
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Rock, Philip J
d679ced0-026b-4876-9c1e-ba89d90e2d5d
Strefford, Jonathan
3782b392-f080-42bf-bdca-8aa5d6ca532f
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Burack, Richard
d2d22d87-512a-452b-8360-bc5a3676fcdb
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda
ba803747-c0ac-409f-a9c2-b61fde009f8c
Valle-Argos, Beatriz
4fddaa71-c0aa-4b95-b464-8bdb592428a2
Chiodin, Giorgia
4b3e9525-b377-4d16-b69a-e05d2e7854fe
Bryant, Dean
10ed83e8-8080-4d9c-bba5-df9d4eec3a10
Taylor, Joe
6a4a31d0-defc-4b85-b4bd-1292b356ef51
Lemm, Elizabeth
f363493b-47ce-4f8e-9e94-272486397cb3
Duriez, Patrick
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Rock, Philip J
d679ced0-026b-4876-9c1e-ba89d90e2d5d
Strefford, Jonathan
3782b392-f080-42bf-bdca-8aa5d6ca532f
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Burack, Richard
d2d22d87-512a-452b-8360-bc5a3676fcdb
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, Freda
ba803747-c0ac-409f-a9c2-b61fde009f8c

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).

Record type: Article

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

Identifiers

Local EPrints ID: 449811
URI: http://eprints.soton.ac.uk/id/eprint/449811
ISSN: 2045-2322
PURE UUID: 20417102-f7ac-41b7-8e3f-5669945f7313
ORCID for Jonathan Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Freda Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

Catalogue record

Date deposited: 18 Jun 2021 16:30
Last modified: 26 Nov 2021 02:48

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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
Author: Graham Packham ORCID iD
Author: Freda Stevenson ORCID iD

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