ABSTRACT
Cell migration is central to evoking a potent immune response. Dendritic cell (DC) migration to lymph nodes is dependent on the interaction of C-type lectin-like receptor 2 (CLEC-2; encoded by the gene Clec1b), expressed by DCs, with podoplanin, expressed by lymph node stromal cells, although the underlying molecular mechanisms remain elusive. Here, we show that CLEC-2-dependent DC migration is controlled by tetraspanin CD37, a membrane-organizing protein. We identified a specific interaction between CLEC-2 and CD37, and myeloid cells lacking CD37 (Cd37−/−) expressed reduced surface CLEC-2. CLEC-2-expressing Cd37−/− DCs showed impaired adhesion, migration velocity and displacement on lymph node stromal cells. Moreover, Cd37−/− DCs failed to form actin protrusions in a 3D collagen matrix upon podoplanin-induced CLEC-2 stimulation, phenocopying CLEC-2-deficient DCs. Microcontact printing experiments revealed that CD37 is required for CLEC-2 recruitment in the membrane to its ligand podoplanin. Finally, Cd37−/− DCs failed to inhibit actomyosin contractility in lymph node stromal cells, thus phenocopying CLEC-2-deficient DCs. This study demonstrates that tetraspanin CD37 controls CLEC-2 membrane organization and provides new molecular insights into the mechanisms underlying CLEC-2-dependent DC migration.
This article has an associated First Person interview with the first author of the paper.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: C.M.d.W., S.v.D., M.G.T., S.E.A., A.B.v.S.; Methodology: C.M.d.W., M.G.T., S.E.A., A.B.v.S.; Validation: C.M.d.W., A.L.M.; Formal analysis: C.M.d.W., A.L.M.; Investigation: C.M.d.W., A.L.M., A.v.d.S., N.D.T., E.J., H.M.M., S.E.A.; Resources: J.A.E., B.N., H.M.M., S.E.A.; Writing - original draft: C.M.d.W.; Writing - review & editing: A.L.M., S.v.D., H.M.M., M.G.T., S.E.A., A.B.v.S.; Visualization: C.M.d.W., A.L.M.; Supervision: C.G.F., M.G.T., S.E.A., A.B.v.S.; Funding acquisition: C.M.d.W., A.L.M., H.M.M., C.G.F., M.G.T., S.E.A., A.B.v.S.
Funding
This work was supported by Erasmus+ [Staff Mobility Grant to C.M.d.W.], Nederlandse Organisatie voor Wetenschappelijk Onderzoek [019.162LW.004 to C.M.d.W.; Scientific Research Spinoza Award to C.G.F.; 864.11.006 and ICI-024.002.009 to A.B.v.S.], the Biotechnology and Biological Sciences Research Council [PhD Studentship to A.L.M.], the Medical Research Council [PhD Studentship to N.D.T.; G0400247 to M.G.T.; MC_U12266B to S.E.A.], Deutsche Forschungsgemeinschaft [SFB1009 A09 to J.A.E.; SFB/TR 240 to B.N.], Arthritis Research UK [19899 to H.M.M.], the European Research Council [269019 to C.G.F.; 724281 to A.B.v.S.], KWF Kankerbestrijding [KUN2009-4402 to C.G.F.; KUN2014-6845 to A.B.v.S.], the British Heart Foundation [FS/08/062/25797 to M.G.T.] and Cancer Research UK [CRUK-A19763 to S.E.A.].
Supplementary information
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.214551.supplemental
- Received January 2, 2018.
- Accepted August 23, 2018.
- © 2018. Published by The Company of Biologists Ltd
Log in using your username and password
Log in through your institution
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$30.00 .
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.
Article navigation
Related articles
Cited by...
More in this TOC section
Similar articles
Other journals from The Company of Biologists
Cell scientist to watch – Serge Mostowy
“Focus on what you think is exciting; in turn, recognise and accept help when it is offered.”
Serge Mostowy heads a lab at the London School of Hygiene & Tropical Medicine, working on the molecular mechanisms underlying bacterial infection and the role of the cytoskeleton in cellular immunity. He shares the story behind his unexpected journey from a background in mathematics, through -omics, sequencing and microscopy to host–pathogen research, and how he has drawn inspiration at each stage from the scientists around him.
Catch up with early-career first authors in our First Person interviews. Recently, we spoke to Bhagawat C. Subramanian, Hannah Arbach, Sudeshna Nag and Patrick Cunningham.
Review – Where, how and why a cell eats itself to death
Shani Bialik, Santosh K. Dasari and Adi Kimchi review recent findings that demonstrate autophagy-dependent cell death in various contexts and begin to elucidate molecular mechanisms that render autophagy a lethal process.
Review – Failure is not an option
André Schneider and Torsten Ochsenreiter discuss recent discoveries regarding the unusual segregation system of the single-unit mitochondrial genome of T. brucei.
Meet the team
Meet the Journal of Cell Science team at conferences throughout October. Executive Editor Sharon Ahmad attends the ASMB meeting in Las Vegas and Reviews Editor Petra Gross will be at the EMBO workshop on ER function in health and disease in Lucca, Italy. Features & Reviews Editor Manuel Breuer will be at the FEBS 2018 Golgi meeting in Sorrento, Italy.
JCS Meeting – Cell dynamics: organelle-cytoskeleton interface
The second in our series of cell dynamics meetings now turns to organelles. This May 2019 meeting in Lisbon, Portugal, aims to bring together scientists studying the interface between organelles and the cytoskeleton at different scales and perspectives using a range of model systems. Find out more and apply for your place here.
Journal news – new fast-track decision process
Do you have a paper with reviews from another journal that you’d like to submit to Journal of Cell Science? We will fast-track your paper and give you an initial decision within a week. Find out more here.
preLights – Transient intracellular acidification regulates the core transcriptional heat shock response
Srivats Venkataramanan highlights a recent pre-print from Allan Drummond and colleagues, showing that a short-lived decrease in the pH of the cellular interior is critical to mount a response to environmental stresses such as increased temperature. This preLight features a response from first author Catherine Triandafillou, outlining the most exciting aspects of the project.
We are also pleased to announce that recent preLights selected for the cell science community will feature regularly as part of our issue Table of Contents.
Articles of interest in our sister journals
GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance
Hue M. La, Ai-Leen Chan, Julien M. D. Legrand, Fernando J. Rossello, Christina G. Gangemi, Antonella Papa, Qiang Cheng, Eric F. Morand, Robin M. Hobbs. Development 2018 145: dev165324
ROCK-nmMyoII, Notch and Neurog3 gene-dosage link epithelial morphogenesis with cell fate in the pancreatic endocrine-progenitor niche
Eric D. Bankaitis, Matthew E. Bechard, Guoqiang Gu, Mark A. Magnuson, Christopher V. E. Wright. Development 2018 145: dev162115