CoChat
Sign Up
Cited by 47Chemokine receptors and signalingLymphatic System and DiseasesImmune Response and Inflammation

Scavenging of soluble and immobilized CCL21 by ACKR4 regulates peripheral dendritic cell emigration

Open access
Bastow, Cameron R., Bunting, Mark D., Kara, Ervin E., McKenzie, Duncan R., Caon, Adriana, Devi, Sapna, Tolley, Lynn, Mueller, Scott N. +7 more·2021·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2025763118PMC PMC8092586
Open this paper in CoChat — free account

Abstract

Significance The immune system relies on coordinated interactions between motile cells guided by molecules known as chemokines. However, processes that control chemokine distribution in complex in vivo microenvironments are poorly understood. Dendritic cells in barrier tissues require the chemokine CCL21 to enter lymphatic vessels during tissue egress. Here, we demonstrate that ACKR4 shapes CCL21 distribution in barrier tissues and prevents leakage of CCL21 from the tissue. Without ACKR4, extracellular CCL21 gradients in barrier sites are saturated and nonfunctional, DCs cannot home directly to lymphatic vessels, and excess soluble CCL21 from peripheral tissues pollutes lymph nodes. The results increase understanding of regulation of dendritic cell egress and chemokine distribution in vivo and raise new questions regarding the function of solubilized CCL21.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.2025763118

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Gradients of CCL21 are maintained by the ACKR4 scavenger receptor expressed by stromal cells in the interstitium.

    “Gradients of CCL21 are maintained by the ACKR4 scavenger receptor that is expressed by stromal cells in the interstitium (104, 105).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [104]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 39

  1. [1]Worbs T., et al., Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J. Exp. Med. 203, 519–527 (2006). [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. [2]Förster R., et al., CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999). [DOI] [PubMed] [Google Scholar]
  3. [3]MartIn-Fontecha A., et al., Regulation of dendritic cell migration to the draining lymph node: Impact on T lymphocyte traffic and priming. J. Exp. Med. 198, 615–621 (2003). [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. [4]Ohl L., et al., CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004). [DOI] [PubMed] [Google Scholar]
  5. [5]Hintzen G., et al., Induction of tolerance to innocuous inhaled antigen relies on a CCR7-dependent dendritic cell-mediated antigen transport to the bronchial lymph node. J. Immunol. 177, 7346–7354 (2006). [DOI] [PubMed] [Google Scholar]
  6. [6]Kriehuber E., et al., Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J. Exp. Med. 194, 797–808 (2001). [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. [7]Gunn M. D., et al., A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 95, 258–263 (1998). [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. [8]Weber M., et al., Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science 339, 328–332 (2013). [DOI] [PubMed] [Google Scholar]
  9. [9]Tal O., et al., DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling. J. Exp. Med. 208, 2141–2153 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. [10]Vaahtomeri K., et al., Locally triggered release of the chemokine CCL21 promotes dendritic cell transmigration across lymphatic endothelia. Cell Rep. 19, 902–909 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. [11]Russo E., et al., Intralymphatic CCL21 promotes tissue egress of dendritic cells through afferent lymphatic vessels. Cell Rep. 14, 1723–1734 (2016). [DOI] [PubMed] [Google Scholar]
  12. [12]Ulvmar M. H., et al., The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients in lymph nodes. Nat. Immunol. 15, 623–630 (2014). [DOI] [PubMed] [Google Scholar]
  13. [13]Schumann K., et al., Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity 32, 703–713 (2010). [DOI] [PubMed] [Google Scholar]
  14. [14]Hjortø G. M., et al., Differential CCR7 targeting in dendritic cells by three naturally occurring CC-chemokines. Front. Immunol. 7, 568 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. [15]Hauser M. A., Legler D. F., Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes. J. Leukoc. Biol. 99, 869–882 (2016). [DOI] [PubMed] [Google Scholar]
  16. [16]Britschgi M. R., Favre S., Luther S. A., CCL21 is sufficient to mediate DC migration, maturation and function in the absence of CCL19. Eur. J. Immunol. 40, 1266–1271 (2010). [DOI] [PubMed] [Google Scholar]
  17. [17]Moussouras N. A., et al., Structural features of an extended C-terminal tail modulate the function of the chemokine CCL21. Biochemistry 59, 1338–1350 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. [18]Heinzel K., Benz C., Bleul C. C., A silent chemokine receptor regulates steady-state leukocyte homing in vivo. Proc. Natl. Acad. Sci. U.S.A. 104, 8421–8426 (2007). [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. [20]Thomson C. A., et al., Expression of the atypical chemokine receptor ACKR4 identifies a novel population of intestinal submucosal fibroblasts that preferentially expresses endothelial cell regulators. J. Immunol. 201, 215–229 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. [21]Lucas B., et al., CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice. Eur. J. Immunol. 45, 574–583 (2015). [DOI] [PubMed] [Google Scholar]
  21. [22]Kara E. E., et al., Atypical chemokine receptor 4 shapes activated B cell fate. J. Exp. Med. 215, 801–813 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. [23]Comerford I., et al., The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses. Blood 116, 4130–4140 (2010). [DOI] [PubMed] [Google Scholar]
  23. [24]Whyte C. E., et al., ACKR4 restrains antitumor immunity by regulating CCL21. J. Exp. Med. 217, e20190634 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. [25]Bunting M. D., et al., CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity. Blood 121, 118–128 (2013). [DOI] [PubMed] [Google Scholar]
  25. [26]Eckert N., Werth K., Willenzon S., Tan L., Förster R., B cell hyperactivation in an Ackr4-deficient mouse strain is not caused by lack of ACKR4 expression. J. Leukoc. Biol. 107, 1155–1166 (2020). [DOI] [PubMed] [Google Scholar]
  26. [27]Merad M., et al., Langerhans cells renew in the skin throughout life under steady-state conditions. Nat. Immunol. 3, 1135–1141 (2002). [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. [28]Janson D. G., Saintigny G., van Adrichem A., Mahé C., El Ghalbzouri A., Different gene expression patterns in human papillary and reticular fibroblasts. J. Invest. Dermatol. 132, 2565–2572 (2012). [DOI] [PubMed] [Google Scholar]
  28. [30]Schwarz J., et al., Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal-to-noise ratio and dependent on GRK6. Curr. Biol. 27, 1314–1325 (2017). [DOI] [PubMed] [Google Scholar]
  29. [31]Chen S. C., et al., Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J. Immunol. 168, 1001–1008 (2002). [DOI] [PubMed] [Google Scholar]
  30. [32]Vargas P., et al., Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells. Nat. Cell Biol. 18, 43–53 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. [33]Dunn L. A., et al., Presentation of the HPV16E7 protein by skin grafts is insufficient to allow graft rejection in an E7-primed animal. Virology 235, 94–103 (1997). [DOI] [PubMed] [Google Scholar]
  32. [34]Yan A., Avraham T., Zampell J. C., Aschen S. Z., Mehrara B. J., Mechanisms of lymphatic regeneration after tissue transfer. PLoS One 6, e17201 (2011). [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. [35]Vassileva G., et al., The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J. Exp. Med. 190, 1183–1188 (1999). [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. [36]Nakano H., Gunn M. D., Gene duplications at the chemokine locus on mouse chromosome 4: Multiple strain-specific haplotypes and the deletion of secondary lymphoid-organ chemokine and EBI-1 ligand chemokine genes in the plt mutation. J. Immunol. 166, 361–369 (2001). [DOI] [PubMed] [Google Scholar]
  35. [37]Kiermaier E., et al., Polysialylation controls dendritic cell trafficking by regulating chemokine recognition. Science 351, 186–190 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. [38]Lorenz N., et al., Plasmin and regulators of plasmin activity control the migratory capacity and adhesion of human T cells and dendritic cells by regulating cleavage of the chemokine CCL21. Immunol. Cell Biol. 94, 955–963 (2016). [DOI] [PubMed] [Google Scholar]
  37. [39]Shevchenko A., Tomas H., Havlis J., Olsen J. V., Mann M., In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat. Protoc. 1, 2856–2860 (2006). [DOI] [PubMed] [Google Scholar]
  38. [41]Weber M., Sixt M., Live cell imaging of chemotactic dendritic cell migration in explanted mouse ear preparations. Methods Mol. Biol. 1013, 215–226 (2013). [DOI] [PubMed] [Google Scholar]
  39. [42]Frazer I. H., et al., Tolerance or immunity to a tumor antigen expressed in somatic cells can be determined by systemic proinflammatory signals at the time of first antigen exposure. J. Immunol. 167, 6180–6187 (2001). [DOI] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Authors
Bastow, C. R., Bunting, M. D., Kara, E. E., McKenzie, D. R., Caon, A., Devi, S., Tolley, L., Mueller, S. N., Frazer, I. H., Harvey, N., Condina, M. R., Young, C., Hoffmann, P., McColl, S. R., & Comerford, I.
Affiliations
  • The University of Adelaide (AU)
  • The University of Melbourne (AU)
  • Translational Research Institute (AU)
  • South Australia Pathology (AU)
  • University of South Australia (AU)
Corresponding author
  • McColl, Shaun R.
  • Comerford, Iain
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2021-04-19
Volume
118
Issue
17
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2025763118
PMC
PMC8092586
OpenAlex
W3154309984
Cited by
47
References
3
Citations by year
2026: 10 · 2025: 3 · 2024: 14 · 2023: 7 · 2022: 7 · 2021: 6
FWCI
3.10
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/aboutpnas/licenses.xhtml (vor, 183 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
CCL21, ACKR4, chemokine scavenging, barrier tissues, chemokine gradients, lymphocyte homing
MeSH terms
Animals, Cell Movement, Dendritic Cells, Lymph Nodes, Mice, Inbred C57BL, Mice, Receptors, CCR, Chemokine CCL21

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review