DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma.
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.
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;
Rada
R
Amin
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;
Frédéric
F
Mourcin
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;
Fabrice
F
Uhel
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;
Céline
C
Pangault
Centre Henri Becquerel, Université de Rouen, Unité Mixte de Recherche U918, INSERM, Rouen, France;
Philippe
P
Ruminy
Université Toulouse III Paul-Sabatier, Toulouse, France; Centre de Physiopathologie de Toulouse Purpan, Unité Mixte de Recherche 1043, INSERM, Toulouse, France; and.
Loic
L
Dupré
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;
Marion
M
Guirriec
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.
Tony
T
Marchand
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;
Thierry
T
Fest
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.
Thierry
T
Lamy
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;
Karin
http://orcid.org/0000-0002-6809-917X
K
Tarte
D015815:Cell Adhesion Molecules / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006031:Glycosylation; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D008224:Lymphoma, Follicular / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D007075:Immunoglobulin M; D037181:Lectins, C-Type; D011947:Receptors, Antigen, B-Cell; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin