Dendritic cells enter lymph vessels by hyaluronan-mediated docking to the endothelial receptor LYVE-1

Johnson, Louise A.; Banerji, Suneale; Lawrance, William; Gileadi, Uzi; Prota, Gennaro; Holder, Kayla A.; Roshorm, Yaowaluck Maprang; Hanke, Tomáš; Cerundolo, Vincenzo; Gale, Nicholas W.; Jackson, David G.

doi:10.1038/ni.3750

Cited by 152 publications

(187 citation statements)

References 52 publications

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“…For example, it would be crucial to establish the relative importance of several other chemokine receptors and their ligands implicated in the migration of DCs, including CX3CL1–CX3CR1 (10) as well as CXCL12-CXCR4 (11). Furthermore, it would be essential to directly compare deficiency of various receptors implicated in DC migration through tissue, such as C-type lectin receptor CLEC-2 (12), hyaluronan (13), or sphingosine 1-phosphate receptors (14). Moreover, it would be important to visualize contributions of divergent signaling cascades, including genes involved in calcium signaling and cytoskeletal organization, in various stages of DC migration (1, 15).…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 Immunoengineering of Hoxb8-Immortalized Progenitor Cells for Revealing CCR7-Mediated Dendritic Cell Signaling and Migration Mechanisms in vivo

et al. 2018

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To present antigens to cognate T cells, dendritic cells (DCs) exploit the chemokine receptor CCR7 to travel from peripheral tissue via afferent lymphatic vessels to directly enter draining lymph nodes through the floor of the subcapsular sinus. Here, we combined unlimited proliferative capacity of conditionally Hoxb8-immortalized hematopoietic progenitor cells with CRISPR/Cas9 technology to create a powerful experimental system to investigate DC migration and function. Hematopoietic progenitor cells from the bone marrow of Cas9-transgenic mice were conditionally immortalized by lentiviral transduction introducing a doxycycline-regulated form of the transcription factor Hoxb8 (Cas9-Hoxb8 cells). These cells could be stably cultured for weeks in the presence of doxycycline and puromycin, allowing us to introduce additional genetic modifications applying CRISPR/Cas9 technology. Importantly, modified Cas9-Hoxb8 cells retained their potential to differentiate in vitro into myeloid cells, and GM-CSF-differentiated Cas9-Hoxb8 cells showed the classical phenotype of GM-CSF-differentiated bone marrow-derived dendritic cells. Following intralymphatic delivery Cas9-Hoxb8 DCs entered the lymph node in a CCR7-dependent manner. Finally, we used two-photon microscopy and imaged Cas9-Hoxb8 DCs that expressed the genetic Ca2+ sensor GCaMP6S to visualize in real-time chemokine-induced Ca2+ signaling of lymph-derived DCs entering the LN parenchyma. Altogether, our study not only allows mechanistic insights in DC migration in vivo, but also provides a platform for the immunoengineering of DCs that, in combination with two-photon imaging, can be exploited to further dissect DC dynamics in vivo.

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Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9 Immunoengineering of Hoxb8-Immortalized Progenitor Cells for Revealing CCR7-Mediated Dendritic Cell Signaling and Migration Mechanisms in vivo

et al. 2018

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“…The interstitial concentration of HA in normal humans is 2 nM (Liu & Zhang, 1998). In addition, naive T lymphocytes do not express HA at the cell surface (Johnson et al, 2017).…”

Section: Discussionmentioning

confidence: 97%

“… e Dendritic cells and activated T lymphocytes enter lymphatic vessels by cell‐surface HA‐mediated docking to LYVE‐1 on lymphatic vessels (Johnson et al, ). The role of the HA‐mediated docking to lymphatic vessels of dendritic cells in adaptive immunity is currently not clear.…”

Section: Discussionmentioning

confidence: 99%

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Development of the LYVE‐1 gene with an acidic‐amino‐acid‐rich (AAAR) domain in evolution is associated with acquisition of lymph nodes and efficient adaptive immunity

Huang

et al. 2017

Journal Cellular Physiology

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CRSBP-1 (mammalian LYVE-1) is a membrane glycoprotein highly expressed in lymphatic endothelial cells (LECs). It has multiple ligands, including hyaluronic acid (HA) and growth factors/cytokines (e.g., PDGF-BB and VEGF-A) containing CRS motifs (clusters of basic amino-acid residues). The ligand binding activities are mediated by Link module and acidic-amino-acid-rich (AAAR) domains, respectively. These CRSBP-1/LYVE-1 ligands have been shown to induce opening of lymphatic intercellular junctions in LEC monolayers and in lymphatic vessels in wild-type mice. We hypothesize that CRSBP-1/LYVE-1 ligands, particularly CRS-containing growth factors/cytokines, are secreted by immune and cancer cells for lymphatic entry during adaptive immune responses and lymphatic metastasis. We have looked into the origin of the Link module and AAAR domain of LYVE-1 in evolution and its association with the development of lymph nodes and efficient adaptive immunity. Lymph nodes represent the only major recent innovation of the adaptive immune systems in evolution particularly to mammals and bird. Here we demonstrate that the development of the LYVE-1 gene with the AAAR domain in evolution is associated with acquisition of lymph nodes and adaptive immunity. LYVE-1 from other species, which have no lymph nodes, lack the AAAR domain and efficient adaptive immunity. Synthetic CRSBP-1 ligands PDGF and VEGF peptides, which contain the CRS motifs of PDGF-BB and VEGF-A, respectively, specifically bind to CRSBP-1 but do not interact with either PDGFβR or VEGFR2. These peptides function as adjuvants by enhancing adaptive immunity of pseudorabies virus (PRV) vaccine in pigs. These results support the notion that LYVE-1 is involved in adaptive immunity in mammals.

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“…The heterogeneous pattern of gene expression may underlie the distinct structure and specialized function of LV. For example, the lymphatic vessel endothelial hyaluronic acid receptor‐1 (LYVE‐1), an LEC‐specific surface marker, is downregulated in the collecting LV but remains high in lymphatic capillaries, likely mediating the trafficking of leukocytes within LV . Podoplanin (PDPN), another LEC marker, and is lowly expressed in skin lymphatic precollectors, involved in lymphocyte trafficking during skin inflammation .…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of tumor lymphangiogenesis: Progress and prospects

Luo

2018

Cancer Science

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Lymphangiogenesis and increased expression of lymphangiogenic growth factors are associated with high rates of lymph node (LN) metastasis and with poor prognosis in some, but not all, solid tumors. In addition to its involvement in metastasis, lymphangiogenesis has been shown to have other roles in tumor pathogenesis, such as the niche function of tumor stem cells and regulatory functions of antitumor immune responses. In contrast, evidence has accumulated that tumor‐induced lymphangiogenesis displays the heterogeneity in gene signature, structure, cellular origins and functional plasticity. This review summarizes the advances in the research on the heterogeneity of tumor lymphangiogenesis and discusses how it may contribute to functional complexity and multiplicity of lymphangiogenesis in tumor progression.

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Dendritic cells enter lymph vessels by hyaluronan-mediated docking to the endothelial receptor LYVE-1

Cited by 152 publications

References 52 publications

CRISPR/Cas9 Immunoengineering of Hoxb8-Immortalized Progenitor Cells for Revealing CCR7-Mediated Dendritic Cell Signaling and Migration Mechanisms in vivo

CRISPR/Cas9 Immunoengineering of Hoxb8-Immortalized Progenitor Cells for Revealing CCR7-Mediated Dendritic Cell Signaling and Migration Mechanisms in vivo

Development of the LYVE‐1 gene with an acidic‐amino‐acid‐rich (AAAR) domain in evolution is associated with acquisition of lymph nodes and efficient adaptive immunity

Heterogeneity of tumor lymphangiogenesis: Progress and prospects

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