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Blood. 2015 Oct 15;126(16):1911-20. doi: 10.1182/blood-2015-04-640912. Epub 2015 Aug 13.

DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma.

Author information

1
Equipe Labellisée Ligue Contre le Cancer, Unité Mixte de Recherche U917, INSERM, Rennes, France; Université Rennes 1, Unité Mixte de Recherche U917, Rennes, France; Etablissement Français du Sang Bretagne, Rennes, France;
2
Equipe Labellisée Ligue Contre le Cancer, Unité Mixte de Recherche U917, INSERM, Rennes, France; Service de réanimation médicale, Centre Hospitalier Universitaire de Rennes, Rennes, France;
3
Equipe Labellisée Ligue Contre le Cancer, Unité Mixte de Recherche U917, INSERM, Rennes, France; Université Rennes 1, Unité Mixte de Recherche U917, Rennes, France; Etablissement Français du Sang Bretagne, Rennes, France; Pôle Biologie, Centre Hospitalier Universitaire de Rennes, Rennes, France;
4
Centre Henri Becquerel, Université de Rouen, Unité Mixte de Recherche U918, INSERM, Rouen, France;
5
Université Toulouse III Paul-Sabatier, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Unité Mixte de Recherche 1043, INSERM, Toulouse, France; and.
6
Equipe Labellisée Ligue Contre le Cancer, Unité Mixte de Recherche U917, INSERM, Rennes, France; Université Rennes 1, Unité Mixte de Recherche U917, Rennes, France; Etablissement Français du Sang Bretagne, Rennes, France; Service d'Hématologie Clinique, Centre Hospitalier Universitaire de Rennes, Rennes, France.

Abstract

Follicular lymphoma (FL) results from the accumulation of malignant germinal center (GC) B cells leading to the development of an indolent and largely incurable disease. FL cells remain highly dependent on B-cell receptor (BCR) signaling and on a specific cell microenvironment, including T cells, macrophages, and stromal cells. Importantly, FL BCR is characterized by a selective pressure to retain surface immunoglobulin M (IgM) BCR despite an active class-switch recombination process, and by the introduction, in BCR variable regions, of N-glycosylation acceptor sites harboring unusual high-mannose oligosaccharides. However, the relevance of these 2 FL BCR features for lymphomagenesis remains unclear. In this study, we demonstrated that IgM(+) FL B cells activated a stronger BCR signaling network than IgG(+) FL B cells and normal GC B cells. BCR expression level and phosphatase activity could both contribute to such heterogeneity. Moreover, we underlined that a subset of IgM(+) FL samples, displaying highly mannosylated BCR, efficiently bound dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), which could in turn trigger delayed but long-lasting BCR aggregation and activation. Interestingly, DC-SIGN was found within the FL cell niche in situ. Finally, M2 macrophages induced a DC-SIGN-dependent adhesion of highly mannosylated IgM(+) FL B cells and triggered BCR-associated kinase activation. Interestingly, pharmacologic BCR inhibitors abolished such crosstalk between macrophages and FL B cells. Altogether, our data support an important role for DC-SIGN-expressing infiltrating cells in the biology of FL and suggest that they could represent interesting therapeutic targets.

PMID:
26272216
PMCID:
PMC4626662
DOI:
10.1182/blood-2015-04-640912
[Indexed for MEDLINE]
Free PMC Article

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