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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion Molecules / immunology*
  • Cell Communication / immunology
  • Coculture Techniques
  • Female
  • Gene Expression Regulation / immunology*
  • Glycosylation
  • Humans
  • Immunoglobulin M / immunology*
  • Lectins, C-Type / immunology*
  • Lymphoma, Follicular / immunology*
  • Lymphoma, Follicular / pathology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Receptors, Antigen, B-Cell / immunology*
  • Receptors, Cell Surface / immunology*
  • Signal Transduction / immunology*
  • Tumor Cells, Cultured


  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Immunoglobulin M
  • Lectins, C-Type
  • Receptors, Antigen, B-Cell
  • Receptors, Cell Surface