CoChat
Sign Up
Cited by 236Immunodeficiency and Autoimmune DisordersImmunotherapy and Immune ResponsesProtein Kinase Regulation and GTPase Signaling

DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses

Open access
Harada, Yosuke, Tanaka, Yoshihiko, Terasawa, Masao, Pieczyk, Markus, Habiro, Katsuyoshi, Katakai, Tomoya, Hanawa-Suetsugu, Kyoko, Kukimoto-Niino, Mutsuko +10 more·2012·Blood
DOI 10.1182/blood-2012-01-407098PMC PMC3418773
Open this paper in CoChat — free accountOpen PDF

Abstract

To migrate efficiently through the interstitium, dendritic cells (DCs) constantly adapt their shape to the given structure of the extracellular matrix and follow the path of least resistance. It is known that this amoeboid migration of DCs requires Cdc42, yet the upstream regulators critical for localization and activation of Cdc42 remain to be determined. Mutations of DOCK8, a member of the atypical guanine nucleotide exchange factor family, causes combined immunodeficiency in humans. In the present study, we show that DOCK8 is a Cdc42-specific guanine nucleotide exchange factor that is critical for interstitial DC migration. By generating the knockout mice, we found that in the absence of DOCK8, DCs failed to accumulate in the lymph node parenchyma for T-cell priming. Although DOCK8-deficient DCs migrated normally on 2-dimensional surfaces, DOCK8 was required for DCs to crawl within 3-dimensional fibrillar networks and to transmigrate through the subcapsular sinus floor. This function of DOCK8 depended on the DHR-2 domain mediating Cdc42 activation. DOCK8 deficiency did not affect global Cdc42 activity. However, Cdc42 activation at the leading edge membrane was impaired in DOCK8-deficient DCs, resulting in a severe defect in amoeboid polarization and migration. Therefore, DOCK8 regulates interstitial DC migration by controlling Cdc42 activity spatially.

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 · 10.1182/blood-2012-01-407098

Cites

2 of 2 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?

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. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673): 245-252.
  2. Cavanagh LL, von Andrian UH. Travellers in many guises: the origins and destinations of dendritic cells. Immunol Cell Biol. 2002;80(5):448-462.
  3. Randolph GJ, Angeli V, Swartz MA. Dendritic-cell trafficking to lymph nodes through lymphatic ves- sels. Nat Rev Immunol. 2005;5(8):617-628.
  4. Fo ¨rster R, Schubel A, Breitfeld D, et al. CCR7 coordinates the primary immune response by es- tablishing functional microenvironments in sec- ondary lymphoid organs. Cell. 1999;99(1):23-33.
  5. Friedl P, Weigelin B. Interstitial leukocyte migra- tion and immune function. Nat Immunol. 2008; 9(9):960-969.
  6. La ¨mmermann T, Bader BL, Monkley SJ, et al. Rapid leukocyte migration by integrin-indepen- dent flowing and squeezing. Nature. 2008; 453(7191):51-55.
  7. Wolf K, Mu ¨ller R, Borgmann S, Bro ¨cker E-B, Friedl P. Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases. Blood. 2003;102(9): 3262-3269.
  8. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature. 2002;420(6916):629-635.
  9. La ¨mmermann T, Renkawitz J, Wu X, Hirsch K, Brakebusch C, Sixt M. Cdc42-dependent leading edge coordination is essential for interstitial den- dritic cell migration. Blood. 2009;113(23):5703- 5710.
  10. Benvenuti F, Hugues S, Warmsley M, et al. Re- quirement of Rac1 and Rac2 expression by ma- ture dendritic cells for T cell priming. Science. 2004;305(5687):1150-1153.
  11. Snapper SB, Meelu P, Nguyen D, et al. WASP deficiency leads to global defects of directed leu- kocyte migration in vitro and in vivo. J Leukoc Biol. 2005;77(6):993-998.
  12. de Noronha S, Hardy S, Sinclair J, et al. Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein. Blood. 2005; 105(4):1590-1597.
  13. Frittoli E, Matteoli G, Palamidessi A, et al. The signalling adaptor Eps8 is an essential actin cap- ping protein for dendritic cell migration. Immunity. 2011;35(3):388-399.
  14. Yamakita Y, Matsumura F, Lipscomb MW, et al. Fascin1 promotes cell migration of mature den- dritic cells. J Immunol. 2011;186(5):2850-2859.
  15. Ruusala A, Aspenstro ¨m P. Isolation and charac- terization of DOCK8, a member of the DOCK180- related regulators of cell morphology. FEBS Lett. 2004;572(1-3):159-166.
  16. Zhang Q, Davis JC, Lamborn IT, et al. Combined immunodeficiency associated with DOCK8 muta- tions. N Engl J Med. 2009;361(21):2046-2056.
  17. Engelhardt KR, McGhee S, Winkler S, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the auto- somal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol. 2009;124(6):1289-1302.
  18. Randall KL, Lambe T, Johnson AL, et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody produc- tion. Nat Immunol. 2009;10(12):1283-1291.
  19. Randall KL, Chan SS, Ma CS, et al. DOCK8 defi- ciency impairs CD8 T cell survival and function in humans and mice. J Exp Med. 2011;208(11): 2305-2320.
  20. Lambe T, Crawfold G, Johnson AL, et al. DOCK8 is essential for T-cell survival and the mainte- nance of CD8ϩ T-cell memory. Eur J Immunol. 2011;41(12):3423-3435.
  21. Nishikimi A, Fukuhara H, Su W, et al. Sequential regulation of DOCK2 dynamics by two phospho- lipids during neutrophil chemotaxis. Science. 2009;324(5925):384-387.
  22. Boscacci RT, Pfeiffer F, Gollmer K, et al. Comprehen- sive analysis of lymph node stroma-expressed Ig superfamily members reveals redundant and nonre- dundant roles for ICAM-1, ICAM-2, and VCAM-1 in lymphocyte homing. Blood. 2010;116(6):915-925.
  23. Ebisuno Y, Katagiri K, Katakai T, et al. Rap1 con- trols lymphocyte adhesion cascade and intersti- tial migration within lymph nodes in RAPL-depen- dent and -independent manners. Blood. 2010; 115(4):804-814.
  24. Otwinowski Z, Minor W. Processing of X-ray dif- fraction data collected in oscillation mode. Meth- ods Enzymol. 1997;276:307-326.
  25. Pflicke H, Sixt M. Preformed portals facilitate den- dritic cell entry into afferent lymphatic vessels. J Exp Med. 2009;206(13):2925-2935.
  26. Stoitzner P, Pfaller K, Sto ¨ssel H, Romani N. A close-up view of migrating langerhans cells in the skin. J Invest Dermatol. 2002;118(1):117-125.
  27. La ¨mmermann T, Sixt M. The microanatomy of T-cell responses. Immunol Rev. 2008;221:26-43.
  28. Baje ´noff M, Egan JG, Koo LY, et al. Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity. 2006; 25(6):989-1001.
  29. Sumen C, Mempel TR, Mazo IB, von Andrian UH. Intravital microscopy: visualizing immunity in con- text. Immunity. 2004;21(3):315-329.
  30. Gretz JE, Norbury CC, Anderson AO, Proudfoot AEI, Shaw S. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenviron- ments in lymph node cortex. J Exp Med. 2000; 192(10):1425-1439.
  31. Gotoh K, Tanaka Y, Nishikimi A, et al. Differential requirement for DOCK2 in migration of plasmacy- toid dendritic cells versus myeloid dendritic cells. Blood. 2008;111(6):2973-2976.
  32. Yang J, Zhang Z, Roe SM, Marshall CJ, Barford D. Activation of Rho GTPases by DOCK exchange fac- tors is mediated by a nucleotide sensor. Science. 2009;325(5946):1398-1402.
  33. Kulkarni K, Yang J, Zhang Z, Barford D. Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nu- cleotide exchange factors. J Biol Chem. 2011; 286(28):25341-25351.
  34. Osmani N, Vitale N, Borg J-P, Etienne-Manneville S. Scrib controls Cdc42 localization and activity to promote cell polarization during astrocyte mi- gration. Curr Biol. 2006;16(24):2395-2405.
  35. Itoh RE, Kurokawa K, Ohba Y, Yoshizaki H, Mochizuki N, Matsuda M. Activation of Rac and Cdc42 video imaged by fluorescent resonance energy transfer-based single-molecule probes in the membrane of living cells. Mol Cell Biol. 2002; 22(18):6582-6591.
  36. Garrett WS, Chen L-M, Kroschewski R, et al. De- velopmental control of endocytosis in dendritic cells by Cdc42. Cell. 2000;102(3):325-334.
  37. Shurin GV, Tourkova IL, Chatta GS, et al. Small Rho GTPases regulate antigen presentation in dendritic cells. J Immunol. 2005;174(6):3394- 3400.
  38. Pulecio J, Petrovic J, Prete F, et al. Cdc42- mediated MTOC polarization in dendritic cells controls targeted delivery of cytokines at the im- mune synapse. J Exp Med. 2010;207(12):2719- 2732.
  39. Braun A, Worbs T, Moschovakis GL, et al. Affer- ent lymph-derived T cells and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migra- tion. Nat Immunol. 2011;12(9):879-887.

Cited by

Sorted by citations

Authors
Harada, Y., Tanaka, Y., Terasawa, M., Pieczyk, M., Habiro, K., Katakai, T., Hanawa-Suetsugu, K., Kukimoto-Niino, M., Nishizaki, T., Shirouzu, M., Duan, X., Uruno, T., Nishikimi, A., Sanematsu, F., Yokoyama, S., Stein, J. V., Kinashi, T., & Fukui, Y.
Affiliations
  • Kyushu University (JP)
  • University of Bern (CH)
  • Kansai Medical University (JP)
  • RIKEN Systems and Structural Biology Center, Yokohama, Japan; and
  • Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo, Japan;
  • Japan Science and Technology Agency (JP)
  • RIKEN (JP)
Corresponding author
  • Harada, Yosuke
  • Tanaka, Yoshihiko
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2012-05-10
Volume
119
Issue
19
Pages
4451-4461
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2012-01-407098
PMC
PMC3418773
OpenAlex
W2069544366
Cited by
236
References
2
Citations by year
2026: 9 · 2025: 10 · 2024: 10 · 2023: 14 · 2022: 12 · 2021: 24 · 2020: 22 · 2019: 16 · 2018: 12 · 2017: 18 · 2016: 23 · 2015: 21 · 2014: 20 · 2013: 21 · 2012: 4
FWCI
9.23
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion)
Funders
  • SENSHIN Medical Research Foundation
  • Japan Society for the Promotion of Science (24590586, 22790469, 24111001, 22370072, 22111003, 22247017, 24111007)
  • Core Research for Evolutional Science and Technology
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
DOCK8, Cdc42, dendritic cell migration, interstitial migration, guanine nucleotide exchange factor, amoeboid migration, lymph node homing, extracellular matrix, T cell priming, combined immunodeficiency
MeSH terms
Animals, Cell Movement, Cells, Cultured, Dendritic Cells, Female, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Cell Culture Techniques, Guanine Nucleotide Exchange Factors, cdc42 GTP-Binding Protein, Mice, Adaptive Immunity, HEK293 Cells

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