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

Abstract

Follicular lymphoma (FL) results fromthe 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 characterizedby aselectivepressure toretainsurfaceimmunoglobulinM(IgM)BCRdespite 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 phosphataseactivity could bothcontribute tosuchheterogeneity.Moreover,weunderlined that a subset of IgM+ FL samples, displaying highly mannosylated BCR, efficiently bound dendritic cell-specific intercellular adhesionmolecule-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, M2macrophages 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 animportant role forDC-SIGN-expressing infiltrating cells in the biology of FL and suggest that they could represent interesting therapeutic targets.