DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity

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...

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Autores principales:	Beatriz Valle-Argos, Giorgia Chiodin, Dean J. Bryant, Joe Taylor, Elizabeth Lemm, Patrick J. Duriez, Philip J. Rock, Jonathan C. Strefford, Francesco Forconi, Richard W. Burack, Graham Packham, Freda K. Stevenson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0f9b4c5e32fc4b8ab9e5de05992b58d9
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spelling	oai:doaj.org-article:0f9b4c5e32fc4b8ab9e5de05992b58d92021-12-02T18:24:54ZDC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity10.1038/s41598-021-91112-72045-2322https://doaj.org/article/0f9b4c5e32fc4b8ab9e5de05992b58d92021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91112-7https://doaj.org/toc/2045-2322Abstract 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.Beatriz Valle-ArgosGiorgia ChiodinDean J. BryantJoe TaylorElizabeth LemmPatrick J. DuriezPhilip J. RockJonathan C. StreffordFrancesco ForconiRichard W. BurackGraham PackhamFreda K. StevensonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Beatriz Valle-Argos Giorgia Chiodin Dean J. Bryant Joe Taylor Elizabeth Lemm Patrick J. Duriez Philip J. Rock Jonathan C. Strefford Francesco Forconi Richard W. Burack Graham Packham Freda K. Stevenson DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
description	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.
format	article
author	Beatriz Valle-Argos Giorgia Chiodin Dean J. Bryant Joe Taylor Elizabeth Lemm Patrick J. Duriez Philip J. Rock Jonathan C. Strefford Francesco Forconi Richard W. Burack Graham Packham Freda K. Stevenson
author_facet	Beatriz Valle-Argos Giorgia Chiodin Dean J. Bryant Joe Taylor Elizabeth Lemm Patrick J. Duriez Philip J. Rock Jonathan C. Strefford Francesco Forconi Richard W. Burack Graham Packham Freda K. Stevenson
author_sort	Beatriz Valle-Argos
title	DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
title_short	DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
title_full	DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
title_fullStr	DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
title_full_unstemmed	DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
title_sort	dc-sign binding to mannosylated b-cell receptors in follicular lymphoma down-modulates receptor signaling capacity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0f9b4c5e32fc4b8ab9e5de05992b58d9
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DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity

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