Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

Sophie E. Acton; Jillian L. Astarita; Deepali Malhotra; Veronika Lukacs-Kornek; Bettina Franz; Paul R. Hess; Zoltan Jakus; Michael Kuligowski; Anne L. Fletcher; Kutlu G. Elpek; Angelique Bellemare-Pelletier; Lindsay Sceats; Erika D. Reynoso; Santiago F. Gonzalez; Daniel B. Graham; Jonathan Chang; Anneli Peters; Matthew Woodruff; Young A. Kim; Wojciech Swat; Takashi Morita; Vijay Kuchroo; Michael C. Carroll; Mark L. Kahn; Kai W. Wucherpfennig; Shannon J. Turley

doi:10.1016/j.immuni.2012.05.022

Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

Sophie E. Acton, Jillian L. Astarita, Deepali Malhotra, Veronika Lukacs-Kornek, Bettina Franz, Paul R. Hess, Zoltan Jakus, Michael Kuligowski, Anne L. Fletcher, Kutlu G. Elpek, Angelique Bellemare-Pelletier, Lindsay Sceats, Erika D. Reynoso, Santiago F. Gonzalez, Daniel B. Graham, Jonathan Chang, Anneli Peters, Matthew Woodruff, Young A. Kim, Wojciech SwatTakashi Morita, Vijay Kuchroo, Michael C. Carroll, Mark L. Kahn, Kai W. Wucherpfennig, Shannon J. Turley

Medical School - Twin Cities Campus

Research output: Contribution to journal › Article › peer-review

238 Scopus citations

Abstract

To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.

Original language	English (US)
Pages (from-to)	276-289
Number of pages	14
Journal	Immunity
Volume	37
Issue number	2
DOIs	https://doi.org/10.1016/j.immuni.2012.05.022
State	Published - Aug 24 2012

Bibliographical note

Funding Information:
The authors are grateful to J. Campbell and B. Vander Lugt for CCR7 knockout mice; to L.-H. Ang, Y. Zheng, and S. Hagen for assistance with microscopy; and to R. Gelman for assistance with statistical analysis. They are also grateful to E. Sahai for critical reading of the manuscript. This work was supported by National Institutes of Health grants R01 DK074500 and P01 AI045757 (to S.J.T.), R01AI073718 and AI061077 (W.S.), and LLS (W.S., D.B.G.); a Wellcome Trust Henry Wellcome Postdoctoral Fellowship (to S.E.A.); a National Science Foundation Graduate Research Fellowship (to J.L.A.); a Benacerraf Postdoctoral Fellowship (to V.L.K.); a National Health Medical Research Council Postdoctoral Biomedical Training Fellowship (to A.L.F.); and a Seventh Framework Programme of the European Union (Marie Curie International Outgoing Fellowship 220044, to S.F.G.).

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Acton, S. E., Astarita, J. L., Malhotra, D., Lukacs-Kornek, V., Franz, B., Hess, P. R., Jakus, Z., Kuligowski, M., Fletcher, A. L., Elpek, K. G., Bellemare-Pelletier, A., Sceats, L., Reynoso, E. D., Gonzalez, S. F., Graham, D. B., Chang, J., Peters, A., Woodruff, M., Kim, Y. A., ... Turley, S. J. (2012). Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2. Immunity, 37(2), 276-289. https://doi.org/10.1016/j.immuni.2012.05.022

Acton, SE, Astarita, JL, Malhotra, D, Lukacs-Kornek, V, Franz, B, Hess, PR, Jakus, Z, Kuligowski, M, Fletcher, AL, Elpek, KG, Bellemare-Pelletier, A, Sceats, L, Reynoso, ED, Gonzalez, SF, Graham, DB, Chang, J, Peters, A, Woodruff, M, Kim, YA, Swat, W, Morita, T, Kuchroo, V, Carroll, MC, Kahn, ML, Wucherpfennig, KW & Turley, SJ 2012, 'Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2', Immunity, vol. 37, no. 2, pp. 276-289. https://doi.org/10.1016/j.immuni.2012.05.022

@article{df29cb51a61342c7a1d046eabf281ac7,

title = "Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2",

abstract = "To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.",

author = "Acton, {Sophie E.} and Astarita, {Jillian L.} and Deepali Malhotra and Veronika Lukacs-Kornek and Bettina Franz and Hess, {Paul R.} and Zoltan Jakus and Michael Kuligowski and Fletcher, {Anne L.} and Elpek, {Kutlu G.} and Angelique Bellemare-Pelletier and Lindsay Sceats and Reynoso, {Erika D.} and Gonzalez, {Santiago F.} and Graham, {Daniel B.} and Jonathan Chang and Anneli Peters and Matthew Woodruff and Kim, {Young A.} and Wojciech Swat and Takashi Morita and Vijay Kuchroo and Carroll, {Michael C.} and Kahn, {Mark L.} and Wucherpfennig, {Kai W.} and Turley, {Shannon J.}",

note = "Funding Information: The authors are grateful to J. Campbell and B. Vander Lugt for CCR7 knockout mice; to L.-H. Ang, Y. Zheng, and S. Hagen for assistance with microscopy; and to R. Gelman for assistance with statistical analysis. They are also grateful to E. Sahai for critical reading of the manuscript. This work was supported by National Institutes of Health grants R01 DK074500 and P01 AI045757 (to S.J.T.), R01AI073718 and AI061077 (W.S.), and LLS (W.S., D.B.G.); a Wellcome Trust Henry Wellcome Postdoctoral Fellowship (to S.E.A.); a National Science Foundation Graduate Research Fellowship (to J.L.A.); a Benacerraf Postdoctoral Fellowship (to V.L.K.); a National Health Medical Research Council Postdoctoral Biomedical Training Fellowship (to A.L.F.); and a Seventh Framework Programme of the European Union (Marie Curie International Outgoing Fellowship 220044, to S.F.G.). ",

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doi = "10.1016/j.immuni.2012.05.022",

language = "English (US)",

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pages = "276--289",

journal = "Immunity",

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TY - JOUR

T1 - Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

AU - Acton, Sophie E.

AU - Astarita, Jillian L.

AU - Malhotra, Deepali

AU - Lukacs-Kornek, Veronika

AU - Franz, Bettina

AU - Hess, Paul R.

AU - Jakus, Zoltan

AU - Kuligowski, Michael

AU - Fletcher, Anne L.

AU - Elpek, Kutlu G.

AU - Bellemare-Pelletier, Angelique

AU - Sceats, Lindsay

AU - Reynoso, Erika D.

AU - Gonzalez, Santiago F.

AU - Graham, Daniel B.

AU - Chang, Jonathan

AU - Peters, Anneli

AU - Woodruff, Matthew

AU - Kim, Young A.

AU - Swat, Wojciech

AU - Morita, Takashi

AU - Kuchroo, Vijay

AU - Carroll, Michael C.

AU - Kahn, Mark L.

AU - Wucherpfennig, Kai W.

AU - Turley, Shannon J.

N1 - Funding Information: The authors are grateful to J. Campbell and B. Vander Lugt for CCR7 knockout mice; to L.-H. Ang, Y. Zheng, and S. Hagen for assistance with microscopy; and to R. Gelman for assistance with statistical analysis. They are also grateful to E. Sahai for critical reading of the manuscript. This work was supported by National Institutes of Health grants R01 DK074500 and P01 AI045757 (to S.J.T.), R01AI073718 and AI061077 (W.S.), and LLS (W.S., D.B.G.); a Wellcome Trust Henry Wellcome Postdoctoral Fellowship (to S.E.A.); a National Science Foundation Graduate Research Fellowship (to J.L.A.); a Benacerraf Postdoctoral Fellowship (to V.L.K.); a National Health Medical Research Council Postdoctoral Biomedical Training Fellowship (to A.L.F.); and a Seventh Framework Programme of the European Union (Marie Curie International Outgoing Fellowship 220044, to S.F.G.).

PY - 2012/8/24

Y1 - 2012/8/24

N2 - To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.

AB - To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.

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ER -

Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

Abstract

Bibliographical note

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