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DC-SIGN expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma
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Edité par CCSD ; American Society of Hematology -
International audience. 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 IgM BCR despite 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 two FL BCR features for lymphomagenesis remains unclear. In this study, we demonstrated that IgM(pos) FL B cells activated a stronger BCR signaling network than IgG(pos) 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(pos) FL samples, displaying highly mannosylated BCR, efficiently bound DC-SIGN, which could in turn trigger a delayed but long-lasting BCR aggregation and activation. Interestingly, DC-SIGN was found within FL cell niche in situ. Finally, M2 macrophages induced a DC-SIGN-dependent adhesion of highly mannosylated IgM(pos) FL B cells and triggered BCR-associated kinase activation. Interestingly, pharmacological 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
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