Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells
Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells
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 high mannoses. We showed previously that the C-type lectins, DC-SIGN and mannose receptor, bound to FL surface Ig (sIg), generating an intracellular Ca(2+) flux. We have now mapped further intracellular pathways activated by DC-SIGN in a range of primary FL cells with detection of phosphorylated ERK1/2, AKT and PLC?2. 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 normal B cells 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 sinusoid-like structures and in some co-localized mononuclear cells, suggesting a role for lectin-expressing cells at this site.
1902-1910
Linley, A.
71f0689d-b688-413c-a4f9-a70e45ea7e0a
Krysov, S.
e783f005-15a1-4ba3-a922-4ed387a3d335
Ponzoni, M.
f481739f-89cb-482c-879a-17a1213431f8
Johnson, P.W.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Packham, G.
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, F.K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
15 October 2015
Linley, A.
71f0689d-b688-413c-a4f9-a70e45ea7e0a
Krysov, S.
e783f005-15a1-4ba3-a922-4ed387a3d335
Ponzoni, M.
f481739f-89cb-482c-879a-17a1213431f8
Johnson, P.W.
3f6068ce-171e-4c2c-aca9-dc9b6a37413f
Packham, G.
fdabe56f-2c58-469c-aadf-38878f233394
Stevenson, F.K.
ba803747-c0ac-409f-a9c2-b61fde009f8c
Linley, A., Krysov, S., Ponzoni, M., Johnson, P.W., Packham, G. and Stevenson, F.K.
(2015)
Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells.
Blood, 126 (16), .
(doi:10.1182/blood-2015-04-640805).
(PMID:26194765)
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 high mannoses. We showed previously that the C-type lectins, DC-SIGN and mannose receptor, bound to FL surface Ig (sIg), generating an intracellular Ca(2+) flux. We have now mapped further intracellular pathways activated by DC-SIGN in a range of primary FL cells with detection of phosphorylated ERK1/2, AKT and PLC?2. 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 normal B cells 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 sinusoid-like structures and in some co-localized mononuclear cells, suggesting a role for lectin-expressing cells at this site.
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Blood 2015 FL Lectin.pdf
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Accepted/In Press date: 9 July 2015
e-pub ahead of print date: 20 July 2015
Published date: 15 October 2015
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 382785
URI: http://eprints.soton.ac.uk/id/eprint/382785
ISSN: 0006-4971
PURE UUID: a3e6bfa0-9677-4d88-8599-490c0c3412a5
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Date deposited: 02 Nov 2015 13:24
Last modified: 15 Mar 2024 03:05
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Author:
A. Linley
Author:
S. Krysov
Author:
M. Ponzoni
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