Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells

Adam Linley, Sergey Krysov, Maurilio Ponzoni, Peter W. Johnson, Graham Packham, Freda K. Stevenson

Research output: Contribution to journalArticlepeer-review

Abstract

The vast majority of cases of follicular lymphoma (FL), but not normal B cells, acquire N-glycosylation sites in the immunoglobulin variable regions during somatic hypermutation. Glycans added to sites are unusual in terminating at highmannoses.We showed previously that the C-type lectins, dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) andmannose receptor,boundtoFLsurfaceimmunoglobulin (sIg), generating an intracellularCa2+flux.Wehavenowmapped further intracellular pathways activatedbyDC-SIGNina rangeofprimaryFLcellswithdetectionof phosphorylated ERK1/2, AKT, and PLCγ2. The SYK inhibitor (tamatinib) or the BTK inhibitor (ibrutinib) each blocked phosphorylation. Activation by DC-SIGN occurred in both IgM+ and IgG+ cases and led to upregulation of MYC expression, with detection in vivo observed in lymph nodes. Unlike cells of chronic lymphocytic leukemia, FL cells expressed relatively high levels of sIg, unchanged by long-term incubation in vitro, indicating no antigen-mediated downregulation in vivo. In contrast, expression of CXCR4 increased in vitro. Engagement of sIg in FL cells or normalBcells by anti-Ig led to endocytosis in vitro as expected, but DC-SIGN, even when cross-linked, did not lead to significant endocytosis of sIg. These findings indicate that lectin binding generates signals via sIg but does not mediate endocytosis, potentially maintaining a supportive antigen-independent signal in vivo. Location of DC-SIGN in FL tissue revealed high levels in sinusoidlike structures and in some colocalized mononuclear cells, suggesting a role for lectin-expressing cells at this site.

Original languageEnglish
Pages (from-to)1902-1910
Number of pages9
JournalBlood
Volume126
Issue number16
DOIs
Publication statusPublished - Oct 15 2015

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

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