Intralymphatic CCL21 promotes tissue egress of dendritic cells through afferent lymphatic vessels
Open accessAbstract
To induce adaptive immunity, dendritic cells (DCs) migrate through afferent lymphatic vessels (LVs) to draining lymph nodes (dLNs). This process occurs in several consecutive steps. Upon entry into lymphatic capillaries, DCs first actively crawl into downstream collecting vessels. From there, they are next passively and rapidly transported to the dLN by lymph flow. Here, we describe a role for the chemokine CCL21 in intralymphatic DC crawling. Performing time-lapse imaging in murine skin, we found that blockade of CCL21-but not the absence of lymph flow-completely abolished DC migration from capillaries toward collecting vessels and reduced the ability of intralymphatic DCs to emigrate from skin. Moreover, we found that in vitro low laminar flow established a CCL21 gradient along lymphatic endothelial monolayers, thereby inducing downstream-directed DC migration. These findings reveal a role for intralymphatic CCL21 in promoting DC trafficking to dLNs, through the formation of a flow-induced gradient.
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CCL21 is the principal chemokine involved in the mobilization and entry of DCs and T cells into lymphatic capillaries.
“The principal chemokine involved in the mobilization and entry of DCs and T cells into lymphatic capillaries is CCL21 (97–99).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [99]
The Introduction and Discussion describe CCL21 as a prominent driver of dendritic-cell migration into lymphatic vessels and trafficking through them. The paper does not establish that CCL21 is the principal chemokine for T-cell mobilization and entry into lymphatic capillaries, so the T-cell portion is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCCL21 produced by capillary LECs is responsible for the directed migration of immunocytes.
“CCL21 produced by capillary LECs is responsible for the directed migration (99).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [99]
The Discussion identifies CCL21 expression by capillary LECs and concludes that CCL21 directs dendritic-cell migration from capillaries toward collecting vessels. It leaves open whether CCL21 also directs other lymph-borne leukocytes, so the claim is broader than the paper’s finding if “immunocytes” includes those cells. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAs immunocytes enter precollecting LVs, they detach from LECs and are carried by fluid flow to the SCS of the draining lymph node.
“As immunocytes enter precollecting LVs, they detach from LECs and are carried by fluid flow to the SCS of the draining lymph node (99, 114).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [99]
The Introduction and Discussion (pages not provided) describe dendritic cells detaching from lymphatic endothelial cells and being transported by lymph flow in collecting vessels. The claim extends this account to immunocytes generally and specifies precollecting vessels and arrival at the draining node’s subcapsular sinus; those details are not established by these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLymph flow in LVs is thought to carry CCL21 to distal sites where it is trapped, probably through binding to podoplanin and heparin sulfate.
“Lymph flow in LVs is thought to carry CCL21 to distal sites where it is trapped, probably through binding to podoplanin and heparin sulfate (87, 99).”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [99]
The section on flow-induced CCL21 shifts hypothesizes that lymph flow moves CCL21 downstream, where it rebinds to lymphatic endothelial cells. The section on immobilized CCL21 identifies heparan sulfate as important for its luminal immobilization. The Discussion suggests podoplanin might contribute to CCL21 presentation, but the paper does not establish that CCL21 binds podoplanin to trap it downstream (page numbers unavailable). (LLM, conf=0.82)
Experimental — accuracy not yet measuredOnce immunocytes access initial LVs, they crawl on the LEC luminal surface, initially randomly and thereafter in the direction of the lymph node.
“Once immunocytes access initial LVs, they crawl on the LEC luminal surface (99, 114, 120) ( Figure 3a ). Crawling is initially random, but thereafter it is in the direction of the lymph node.”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [99]
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Bao, X., Moseman, E. A., Saito, H., Petryanik, B., Thiriot, A., Hatakeyama, S., Ito, Y., Kawashima, H., Yamaguchi, Y., Lowe, J. B., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.10.018 · Cited by 167 · see citing works
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Research works printed but not linked: 2
- Jat, P.S., Noble, M.D., Ataliotis, P., Tanaka, Y., Yannoutsos, N., Larsen, L., and Kioussis, D. (1991). Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse. Proc. Natl. Acad. Sci. USA 88, 5096-5100.
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González-Loyola, A., & Petrova, T. V. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.12.005 · Cited by 89 · see citing works
Transport and Immune Functions of the Lymphatic System.
Davis, M. J., Zawieja, S. D., & King, P. D. (2025) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022724-104908 · Cited by 42 · see citing works
- Authors
- Russo, E., Teijeira, A., Vaahtomeri, K., Willrodt, A.-H., Bloch, J. S., Nitschké, M., Santambrogio, L., Kerjaschki, D., Sixt, M., & Halin, C.
- Affiliations
- ETH Zurich (CH)
- Institute of Science and Technology Austria (AT)
- Albert Einstein College of Medicine (US)
- Medical University of Vienna (AT)
- Corresponding author
- Halin, Cornelia
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 14
- Issue
- 7
- Pages
- 1723-1734
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2263813704
- Cited by
- 193
- References
- 1
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 17 · 2023: 13 · 2022: 13 · 2021: 26 · 2020: 22 · 2019: 20 · 2018: 19 · 2017: 19 · 2016: 6
- FWCI
- 11.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
- ETH Zürich Research Collection
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
- Keywords
- CCL21, dendritic cell migration, afferent lymphatic vessels, lymphatic capillaries, collecting lymphatic vessels, lymph flow, chemokine gradients, lymphatic endothelium, draining lymph nodes, skin, time-lapse imaging
- MeSH terms
- Animals, Bone Marrow Cells, Cell Movement, Dendritic Cells, Ear, Endothelium, Lymphatic, Lymph Nodes, Mice, Inbred C57BL, Mice, Transgenic, Rheology, Skin, Gene Expression, Lymphatic Vessels, Mice, Chemokine CCL21, Time-Lapse Imaging
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