ABSTRACT Dendritic cells (DCs) are the key link between innate immunity and adaptive immunity and play crucial roles in both the promotion of immune defense and the maintenance of immune

tolerance. The trafficking of distinct DC subsets across lymphoid and nonlymphoid tissues is essential for DC-dependent activation and regulation of inflammation and immunity. DC chemotaxis

and migration are triggered by interactions between chemokines and their receptors and regulated by multiple intracellular mechanisms, such as protein modification, epigenetic reprogramming,

metabolic remodeling, and cytoskeletal rearrangement, in a tissue-specific manner. Dysregulation of DC migration may lead to abnormal positioning or activation of DCs, resulting in an

routes and immunological consequences of distinct DC subsets, the molecular basis and regulatory mechanisms of migratory signaling in DCs, and the association of DC migration with the

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Article 17 September 2024 DENDRITIC CELL MATURATION IN CANCER Article 07 February 2025 T CELL RECEPTOR SIGNALING STRENGTH ESTABLISHES THE CHEMOTACTIC PROPERTIES OF EFFECTOR CD8+ T CELLS THAT

CONTROL TISSUE-RESIDENCY Article Open access 04 July 2023 REFERENCES * Worbs T, Hammerschmidt SI, Forster R. Dendritic cell migration in health and disease. Nat Rev Immunol. 2017;17:30–48.

Article  CAS  PubMed  Google Scholar  * Qian C, Cao X. Dendritic cells in the regulation of immunity and inflammation. Semin Immunol. 2018;35:3–11. Article  CAS  PubMed  Google Scholar  *

Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 2015;16:343–53. Article  CAS  PubMed  PubMed Central  Google Scholar  * Steinman RM. Decisions

about dendritic cells: past, present, and future. Annu Rev. Immunol. 2012;30:1–22. Article  CAS  PubMed  Google Scholar  * Randolph GJ, Ochando J, Partida-Sanchez S. Migration of dendritic

cell subsets and their precursors. Annu Rev Immunol. 2008;26:293–316. Article  CAS  PubMed  Google Scholar  * Kashem SW, Haniffa M, Kaplan DH. Antigen-Presenting Cells in the Skin. Annu Rev

Immunol. 2017;35:469–99. Article  CAS  PubMed  Google Scholar  * Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20. Article  CAS  PubMed  Google

Scholar  * Förster R, Schubel A, Breitfeld D, Kremmer E, Renner-Müller I, Wolf E, et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in

secondary lymphoid organs. Cell. 1999;99:23–33. Article  PubMed  Google Scholar  * Jang MH, Sougawa N, Tanaka T, Hirata T, Hiroi T, Tohya K, et al. CCR7 is critically important for migration

of dendritic cells in intestinal lamina propria to mesenteric lymph nodes. J. Immunol. 2006;176:803–10. Article  CAS  PubMed  Google Scholar  * Gunn MD, Kyuwa S, Tam C, Kakiuchi T,

Matsuzawa A, Williams LT, et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med. 1999;189:451–60.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Ulvmar MH, Werth K, Braun A, Kelay P, Hub E, Eller K, et al. The atypical chemokine receptor CCRL1 shapes functional CCL21 gradients

in lymph nodes. Nat Immunol. 2014;15:623–30. Article  CAS  PubMed  Google Scholar  * Braun A, Worbs T, Moschovakis GL, Halle S, Hoffmann K, Bölter J, et al. Afferent lymph-derived T cells

and DCs use different chemokine receptor CCR7-dependent routes for entry into the lymph node and intranodal migration. Nat Immunol. 2011;12:879–87. Article  CAS  PubMed  Google Scholar  *

Ohl L, Mohaupt M, Czeloth N, Hintzen G, Kiafard Z, Zwirner J, et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity. 2004;21:279–88.

Article  CAS  PubMed  Google Scholar  * Hintzen G, Ohl L, del Rio ML, Rodriguez-Barbosa JI, Pabst O, Kocks JR, 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. 2006;177:7346–54. Article  CAS  PubMed  Google Scholar  * Worbs T, Bode U, Yan S, Hoffmann

MW, Hintzen G, Bernhardt G, et al. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J Exp Med. 2006;203:519–27. Article  CAS 

PubMed  PubMed Central  Google Scholar  * Davalos-Misslitz AC, Rieckenberg J, Willenzon S, Worbs T, Kremmer E, Bernhardt G, et al. Generalized multi-organ autoimmunity in CCR7-deficient

mice. Eur J Immunol. 2007;37:613–22. Article  CAS  PubMed  Google Scholar  * Kurobe H, Liu C, Ueno T, Saito F, Ohigashi I, Seach N, et al. CCR7-dependent cortex-to-medulla migration of

positively selected thymocytes is essential for establishing central tolerance. Immunity. 2006;24:165–77. Article  CAS  PubMed  Google Scholar  * Cao X, Zhang W, Wan T, He L, Chen T, Yuan Z,

et al. Molecular cloning and characterization of a novel CXC chemokine macrophage inflammatory protein-2 gamma chemoattractant for human neutrophils and dendritic cells. J Immunol.

2000;165:2588–95. Article  CAS  PubMed  Google Scholar  * Shellenberger TD, Wang M, Gujrati M, Jayakumar A, Strieter RM, Burdick MD, et al. BRAK/CXCL14 is a potent inhibitor of angiogenesis

and a chemotactic factor for immature dendritic cells. Cancer Res. 2004;64:8262–70. Article  CAS  PubMed  Google Scholar  * Schaerli P, Willimann K, Ebert LM, Walz A, Moser B. Cutaneous

CXCL14 targets blood precursors to epidermal niches for Langerhans cell differentiation. Immunity. 2005;23:331–42. Article  CAS  PubMed  Google Scholar  * Lee J, Zhang J, Chung YJ, Kim JH,

Kook CM, González-Navajas JM, et al. Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses. Elife 2020;9:e49416 (1–30). * Ho

AW, Prabhu N, Betts RJ, Ge MQ, Dai X, Hutchinson PE, et al. Lung CD103+ dendritic cells efficiently transport influenza virus to the lymph node and load viral antigen onto MHC class I for

presentation to CD8 T cells. J Immunol. 2011;187:6011–21. Article  CAS  PubMed  Google Scholar  * Helft J, Manicassamy B, Guermonprez P, Hashimoto D, Silvin A, Agudo J, et al.

Cross-presenting CD103+ dendritic cells are protected from influenza virus infection. J Clin Invest. 2012;122:4037–47. Article  CAS  PubMed  PubMed Central  Google Scholar  * Shekhar S, Peng

Y, Wang S, Yang X. CD103+ lung dendritic cells (LDCs) induce stronger Th1/Th17 immunity to a bacterial lung infection than CD11b(hi) LDCs. Cell Mol Immunol. 2018;15:377–87. Article  CAS 

PubMed  Google Scholar  * Ding Y, Guo Z, Liu Y, Li X, Zhang Q, Xu X, et al. The lectin Siglec-G inhibits dendritic cell cross-presentation by impairing MHC class I-peptide complex formation.

Nat Immunol. 2016;17:1167–75. Article  CAS  PubMed  Google Scholar  * Ng SL, Teo YJ, Setiagani YA, Karjalainen K, Ruedl C. Type 1 conventional CD103(+) dendritic cells control effector

CD8(+) T cell migration, survival, and memory responses during influenza infection. Front Immunol. 2018;9:3043. Article  CAS  PubMed  PubMed Central  Google Scholar  * Henri S, Poulin LF,

Tamoutounour S, Ardouin L, Guilliams M, de Bovis B, et al. CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells.

J Exp Med. 2010;207:189–206. Article  CAS  PubMed  PubMed Central  Google Scholar  * Bedoui S, Whitney PG, Waithman J, Eidsmo L, Wakim L, Caminschi I, et al. Cross-presentation of viral and

self antigens by skin-derived CD103+ dendritic cells. Nat Immunol. 2009;10:488–95. Article  CAS  PubMed  Google Scholar  * Stary G, Olive A, Radovic-Moreno AF, Gondek D, Alvarez D, Basto PA,

et al. VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science. 2015;348:aaa8205. Article  PubMed  PubMed Central  CAS  Google

Scholar  * Sokol CL, Camire RB, Jones MC, Luster AD. The chemokine receptor CCR8 promotes the migration of dendritic cells into the lymph node parenchyma to initiate the allergic immune

response. Immunity. 2018;49:449–63. Article  CAS  PubMed  PubMed Central  Google Scholar  * Moon HG, Kim SJ, Jeong JJ, Han SS, Jarjour NN, Lee H, et al. Airway epithelial cell-derived colony

stimulating factor-1 promotes allergen sensitization. Immunity. 2018;49:275–87.e275. Article  CAS  PubMed  PubMed Central  Google Scholar  * Moon HG, Kim SJ, Lee MK, Kang H, Choi HS,

Harijith A, et al. Colony-stimulating factor 1 and its receptor are new potential therapeutic targets for allergic asthma. Allergy. 2020;75:357–69. Article  CAS  PubMed  Google Scholar  *

Perner C, Flayer CH, Zhu X, Aderhold PA, Dewan Z, Voisin T, et al. Substance P release by sensory neurons triggers dendritic cell migration and initiates the type-2 immune response to

allergens. Immunity. 2020;53:1063–77. Article  CAS  PubMed  PubMed Central  Google Scholar  * Leon B, Lopez-Bravo M, Ardavin C. Monocyte-derived dendritic cells formed at the infection site

control the induction of protective T helper 1 responses against Leishmania. Immunity. 2007;26:519–31. Article  CAS  PubMed  Google Scholar  * Tamoutounour S, Guilliams M, Montanana Sanchis

F, Liu H, Terhorst D, Malosse C, et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity. 2013;39:925–38.

Article  CAS  PubMed  Google Scholar  * Plantinga M, Guilliams M, Vanheerswynghels M, Deswarte K, Branco-Madeira F, Toussaint W, et al. Conventional and monocyte-derived CD11b(+) dendritic

cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity. 2013;38:322–35. Article  CAS  PubMed  Google Scholar  * Zigmond E, Varol C, Farache J,

Elmaliah E, Satpathy AT, Friedlander G, et al. Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity.

2012;37:1076–90. Article  CAS  PubMed  Google Scholar  * Nakano H, Lin KL, Yanagita M, Charbonneau C, Cook DN, Kakiuchi T, et al. Blood-derived inflammatory dendritic cells in lymph nodes

stimulate acute T helper type 1 immune responses. Nat Immunol. 2009;10:394–402. Article  CAS  PubMed  PubMed Central  Google Scholar  * Lian J, Ozga AJ, Sokol CL, Luster AD. Targeting lymph

node niches enhances type 1 immune responses to immunization. Cell Rep. 2020;31:107679. Article  CAS  PubMed  PubMed Central  Google Scholar  * Cheong C, Matos I, Choi JH, Dandamudi DB,

Shrestha E, Longhi MP, et al. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell. 2010;143:416–29. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Bosteels C, Neyt K, Vanheerswynghels M, van Helden MJ, Sichien D, Debeuf N, et al. Inflammatory type 2 cDCs acquire features of cDC1s and macrophages to

orchestrate immunity to respiratory virus infection. Immunity. 2020;52:1039–56. Article  CAS  PubMed  PubMed Central  Google Scholar  * Seth S, Oberdörfer L, Hyde R, Hoff K, Thies V, Worbs

T, et al. CCR7 essentially contributes to the homing of plasmacytoid dendritic cells to lymph nodes under steady-state as well as inflammatory conditions. J Immunol. 2011;186:3364–72.

Article  CAS  PubMed  Google Scholar  * Vermi W, Riboldi E, Wittamer V, Gentili F, Luini W, Marrelli S, et al. Role of ChemR23 in directing the migration of myeloid and plasmacytoid

dendritic cells to lymphoid organs and inflamed skin. J Exp Med. 2005;201:509–15. Article  CAS  PubMed  PubMed Central  Google Scholar  * Vanbervliet B, Bendriss-Vermare N, Massacrier C,

Homey B, de Bouteiller O, Brière F, et al. The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1

(SDF-1)/CXCL12. J Exp Med. 2003;198:823–30. Article  CAS  PubMed  PubMed Central  Google Scholar  * Krug A, Uppaluri R, Facchetti F, Dorner BG, Sheehan KC, Schreiber RD, et al. IFN-producing

cells respond to CXCR3 ligands in the presence of CXCL12 and secrete inflammatory chemokines upon activation. J Immunol. 2002;169:6079–83. Article  CAS  PubMed  Google Scholar  * Diacovo

TG, Blasius AL, Mak TW, Cella M, Colonna M. Adhesive mechanisms governing interferon-producing cell recruitment into lymph nodes. J Exp Med. 2005;202:687–96. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Umemoto E, Otani K, Ikeno T, Verjan Garcia N, Hayasaka H, Bai Z, et al. Constitutive plasmacytoid dendritic cell migration to the splenic white pulp is

cooperatively regulated by CCR7- and CXCR4-mediated signaling. J Immunol. 2012;189:191–9. Article  CAS  PubMed  Google Scholar  * Sisirak V, Vey N, Vanbervliet B, Duhen T, Puisieux I, Homey

B, et al. CCR6/CCR10-mediated plasmacytoid dendritic cell recruitment to inflamed epithelia after instruction in lymphoid tissues. Blood. 2011;118:5130–40. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Pascale F, Contreras V, Bonneau M, Courbet A, Chilmonczyk S, Bevilacqua C, et al. Plasmacytoid dendritic cells migrate in afferent skin lymph. J Immunol.

2008;180:5963–72. Article  CAS  PubMed  Google Scholar  * Yrlid U, Milling SW, Miller JL, Cartland S, Jenkins CD, MacPherson GG. Regulation of intestinal dendritic cell migration and

activation by plasmacytoid dendritic cells, TNF-alpha and type 1 IFNs after feeding a TLR7/8 ligand. J Immunol. 2006;176:5205–12. Article  CAS  PubMed  Google Scholar  * Wendland M, Czeloth

N, Mach N, Malissen B, Kremmer E, Pabst O, et al. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc Natl Acad Sci USA. 2007;104:6347–52. Article  CAS 

PubMed  PubMed Central  Google Scholar  * Clahsen T, Pabst O, Tenbrock K, Schippers A, Wagner N. Localization of dendritic cells in the gut epithelium requires MAdCAM-1. Clin Immunol.

2015;156:74–84. Article  CAS  PubMed  Google Scholar  * Swiecki M, Miller HL, Sesti-Costa R, Cella M, Gilfillan S, Colonna M. Microbiota induces tonic CCL2 systemic levels that control pDC

trafficking in steady state. Mucosal Immunol. 2017;10:936–45. Article  CAS  PubMed  Google Scholar  * Heath WR, Carbone FR. The skin-resident and migratory immune system in steady state and

memory: innate lymphocytes, dendritic cells and T cells. Nat Immunol. 2013;14:978–85. Article  CAS  PubMed  Google Scholar  * Gallego, C et al. CXCR4 signaling controls dendritic cell

location and activation at steady-state and in inflammation. Blood 2021;137:2770–84. * Cao X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and

disease. Nat Rev Immunol. 2016;16:35–50. Article  CAS  PubMed  Google Scholar  * Forster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev

Immunol. 2008;8:362–71. Article  PubMed  CAS  Google Scholar  * Girard JP, Moussion C, Forster R. HEVs, lymphatics and homeostatic immune cell trafficking in lymph nodes. Nat Rev Immunol.

2012;12:762–73. Article  CAS  PubMed  Google Scholar  * Byers MA, Calloway PA, Shannon L, Cunningham HD, Smith S, Li F, et al. Arrestin 3 mediates endocytosis of CCR7 following ligation of

CCL19 but not CCL21. J Immunol. 2008;181:4723–32. Article  CAS  PubMed  Google Scholar  * Haessler U, Pisano M, Wu M, Swartz MA. Dendritic cell chemotaxis in 3D under defined chemokine

gradients reveals differential response to ligands CCL21 and CCL19. Proc Natl Acad Sci USA. 2011;108:5614–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Weber M, Hauschild R,

Schwarz J, Moussion C, de Vries I, Legler DF, et al. Interstitial dendritic cell guidance by haptotactic chemokine gradients. Science. 2013;339:328–32. Article  CAS  PubMed  Google Scholar 

* Sánchez-Sánchez N, Riol-Blanco L, de la Rosa G, Puig-Kröger A, García-Bordas J, Martín D, et al. Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature

dendritic cells. Blood. 2004;104:619–25. Article  PubMed  CAS  Google Scholar  * Riol-Blanco L, Sánchez-Sánchez N, Torres A, Tejedor A, Narumiya S, Corbí AL, et al. The chemokine receptor

CCR7 activates in dendritic cells two signaling modules that independently regulate chemotaxis and migratory speed. J Immunol. 2005;174:4070–80. Article  CAS  PubMed  Google Scholar  * Liu

S, Wu J, Zhang T, Qian B, Wu P, Li L, et al. Complement C1q chemoattracts human dendritic cells and enhances migration of mature dendritic cells to CCL19 via activation of AKT and MAPK

pathways. Mol Immunol. 2008;46:242–9. Article  CAS  PubMed  Google Scholar  * Guo Z, Zhang M, Tang H, Cao X. Fas signal links innate and adaptive immunity by promoting dendritic-cell

secretion of CC and CXC chemokines. Blood. 2005;106:2033–41. Article  CAS  PubMed  Google Scholar  * Fruman DA, Bismuth G. Fine tuning the immune response with PI3K. Immunol Rev.

2009;228:253–72. Article  CAS  PubMed  Google Scholar  * Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, et al. Defective dendritic cell migration and activation of adaptive

immunity in PI3Kgamma-deficient mice. EMBO J. 2004;23:3505–15. Article  PubMed  PubMed Central  CAS  Google Scholar  * Matheu MP, Deane JA, Parker I, Fruman DA, Cahalan MD. Class IA

phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node. J Immunol. 2007;179:2261–9. Article  CAS  PubMed  Google Scholar  * Chin YR, Toker A. The actin-bundling

protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol Cell. 2010;38:333–44. Article  CAS  PubMed  PubMed Central  Google Scholar  * Krycer JR,

Sharpe LJ, Luu W, Brown AJ. The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab. 2010;21:268–76. Article  CAS  PubMed  Google Scholar  * Baus D, Heermeier K,

De Hoop M, Metz-Weidmann C, Gassenhuber J, Dittrich W, et al. Identification of a novel AS160 splice variant that regulates GLUT4 translocation and glucose-uptake in rat muscle cells. Cell

Signal. 2008;20:2237–46. Article  CAS  PubMed  Google Scholar  * Liu J, Cao X. Regulatory dendritic cells in autoimmunity: A comprehensive review. J Autoimmun. 2015;63:1–12. Article  CAS 

PubMed  Google Scholar  * Liu J, Han C, Xie B, Wu Y, Liu S, Chen K, et al. Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination

of the regulator NEMO. Nat Immunol. 2014;15:612–22. Article  CAS  PubMed  Google Scholar  * Zidar DA, Violin JD, Whalen EJ, Lefkowitz RJ. Selective engagement of G protein coupled receptor

kinases (GRKs) encodes distinct functions of biased ligands. Proc Natl Acad Sci USA. 2009;106:9649–54. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kohout TA, Nicholas SL, Perry

SJ, Reinhart G, Junger S, Struthers RS. Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC

chemokine receptor 7. J Biol Chem. 2004;279:23214–22. Article  CAS  PubMed  Google Scholar  * Marsland BJ, Bättig P, Bauer M, Ruedl C, Lässing U, Beerli RR, et al. CCL19 and CCL21 induce a

potent proinflammatory differentiation program in licensed dendritic cells. Immunity. 2005;22:493–505. Article  CAS  PubMed  Google Scholar  * Yanagawa Y, Onoe K. CCR7 ligands induce rapid

endocytosis in mature dendritic cells with concomitant up-regulation of Cdc42 and Rac activities. Blood. 2003;101:4923–9. Article  CAS  PubMed  Google Scholar  * Baratin M, Foray C, Demaria

O, Habbeddine M, Pollet E, Maurizio J, et al. Homeostatic NF-kappaB signaling in steady-state migratory dendritic cells regulates immune homeostasis and tolerance. Immunity. 2015;42:627–39.

Article  CAS  PubMed  Google Scholar  * Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi-Castagnoli P. Dendritic cell survival and maturation are regulated by different signaling

pathways. J Exp Med. 1998;188:2175–80. Article  CAS  PubMed  PubMed Central  Google Scholar  * Krappmann D, Wegener E, Sunami Y, Esen M, Thiel A, Mordmuller B, et al. The IkappaB kinase

complex and NF-kappaB act as master regulators of lipopolysaccharide-induced gene expression and control subordinate activation of AP-1. Mol Cell Biol. 2004;24:6488–500. Article  CAS  PubMed

  PubMed Central  Google Scholar  * Yamakita Y, Matsumura F, Lipscomb MW, Chou PC, Werlen G, Burkhardt JK, et al. Fascin1 promotes cell migration of mature dendritic cells. J Immunol.

2011;186:2850–9. Article  CAS  PubMed  Google Scholar  * Hagerbrand K, Westlund J, Yrlid U, Agace W, Johansson-Lindbom B. MyD88 signaling regulates steady-state migration of intestinal

CD103+ dendritic cells independently of TNF-alpha and the gut microbiota. J Immunol. 2015;195:2888–99. Article  PubMed  CAS  Google Scholar  * Wang L, Liu Q, Sun Q, Zhang C, Chen T, Cao X.

TLR4 signaling in cancer cells promotes chemoattraction of immature dendritic cells via autocrine CCL20. Biochem Biophys Res Commun. 2008;366:852–6. Article  CAS  PubMed  Google Scholar  *

Chen T, Guo J, Yang M, Han C, Zhang M, Chen W, et al. Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression.

Blood. 2004;103:413–21. Article  CAS  PubMed  Google Scholar  * Liu Q, Chen T, Chen G, Shu X, Sun A, Ma P, et al. Triptolide impairs dendritic cell migration by inhibiting CCR7 and COX-2

expression through PI3-K/Akt and NF-kappaB pathways. Mol Immunol. 2007;44:2686–96. Article  CAS  PubMed  Google Scholar  * Liu Q, Chen T, Chen G, Li N, Wang J, Ma P, et al. Immunosuppressant

triptolide inhibits dendritic cell-mediated chemoattraction of neutrophils and T cells through inhibiting Stat3 phosphorylation and NF-kappaB activation. Biochem Biophys Res Commun.

2006;345:1122–30. Article  CAS  PubMed  Google Scholar  * Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell.

2011;146:772–84. Article  CAS  PubMed  PubMed Central  Google Scholar  * Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, et al. Hypoxia-inducible factors enhance the

effector responses of CD8(+) T cells to persistent antigen. Nat Immunol. 2013;14:1173–82. Article  CAS  PubMed  PubMed Central  Google Scholar  * Colgan SP, Furuta GT, Taylor CT. Hypoxia and

Innate Immunity: keeping Up with the HIFsters. Annu Rev Immunol. 2020;38:341–63. Article  CAS  PubMed  PubMed Central  Google Scholar  * McGettrick AF, O’Neill LAJ. The role of HIF in

Immunity and Inflammation. Cell Metab. 2020;32:524–36. Article  CAS  PubMed  Google Scholar  * Nizet V, Johnson RS. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol.

2009;9:609–17. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kohler T, Reizis B, Johnson RS, Weighardt H, Forster I. Influence of hypoxia-inducible factor 1alpha on dendritic cell

differentiation and migration. Eur J Immunol. 2012;42:1226–36. Article  PubMed  PubMed Central  CAS  Google Scholar  * Ricciardi A, Elia AR, Cappello P, Puppo M, Vanni C, Fardin P, et al.

Transcriptome of hypoxic immature dendritic cells: modulation of chemokine/receptor expression. Mol Cancer Res. 2008;6:175–85. Article  CAS  PubMed  Google Scholar  * Cramer T, Yamanishi Y,

Clausen BE, Förster I, Pawlinski R, Mackman N, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003;112:645–57. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Liu J, Zhang X, Chen K, Cheng Y, Liu S, Xia M, et al. CCR7 chemokine receptor-inducible lnc-Dpf3 restrains dendritic cell migration by inhibiting HIF-1alpha-mediated glycolysis.

Immunity. 2019;50:600–15. Article  CAS  PubMed  Google Scholar  * Suzuki S, Honma K, Matsuyama T, Suzuki K, Toriyama K, Akitoyo I, et al. Critical roles of interferon regulatory factor 4 in

CD11bhighCD8alpha- dendritic cell development. Proc Natl Acad. Sci USA. 2004;101:8981–6. Article  CAS  PubMed  PubMed Central  Google Scholar  * Tamura T, Tailor P, Yamaoka K, Kong HJ,

Tsujimura H, O'Shea JJ, et al. IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J Immunol. 2005;174:2573–81. Article  CAS  PubMed

  Google Scholar  * Edelson BT, KC W, Juang R, Kohyama M, Benoit LA, Klekotka PA, et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+

conventional dendritic cells. J Exp Med. 2010;207:823–36. Article  CAS  PubMed  PubMed Central  Google Scholar  * Bajana S, Roach K, Turner S, Paul J, Kovats S. IRF4 promotes cutaneous

dendritic cell migration to lymph nodes during homeostasis and inflammation. J Immunol. 2012;189:3368–77. Article  CAS  PubMed  Google Scholar  * Persson EK, Uronen-Hansson H, Semmrich M,

Rivollier A, Hägerbrand K, Marsal J, et al. IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation. Immunity. 2013;38:958–69.

Article  CAS  PubMed  Google Scholar  * Schlitzer A, McGovern N, Teo P, Zelante T, Atarashi K, Low D, et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse

control mucosal IL-17 cytokine responses. Immunity. 2013;38:970–83. Article  CAS  PubMed  PubMed Central  Google Scholar  * Akbari M, Honma K, Kimura D, Miyakoda M, Kimura K, Matsuyama T, et

al. IRF4 in dendritic cells inhibits IL-12 production and controls Th1 immune responses against Leishmania major. J Immunol. 2014;192:2271–9. Article  CAS  PubMed  Google Scholar  * Vander

Lugt B, Khan AA, Hackney JA, Agrawal S, Lesch J, Zhou M, et al. Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation. Nat Immunol. 2014;15:161–7.

Article  CAS  Google Scholar  * Xiao K, Sun J, Kim J, Rajagopal S, Zhai B, Villén J, et al. Global phosphorylation analysis of beta-arrestin-mediated signaling downstream of a seven

transmembrane receptor (7TMR). Proc Natl Acad Sci USA. 2010;107:15299–304. Article  CAS  PubMed  PubMed Central  Google Scholar  * Eichel K, Jullie D, von Zastrow M. beta-Arrestin drives MAP

kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol. 2016;18:303–10. Article  CAS  PubMed  PubMed Central  Google Scholar  * Hauser MA, Schaeuble K,

Kindinger I, Impellizzieri D, Krueger WA, Hauck CR, et al. Inflammation-induced CCR7 oligomers form scaffolds to integrate distinct signaling pathways for efficient cell migration. Immunity.

2016;44:59–72. Article  CAS  PubMed  Google Scholar  * Otero C, Groettrup M, Legler DF. Opposite fate of endocytosed CCR7 and its ligands: recycling versus degradation. J Immunol.

2006;177:2314–23. Article  CAS  PubMed  Google Scholar  * Schaeuble K, Hauser MA, Rippl AV, Bruderer R, Otero C, Groettrup M, et al. Ubiquitylation of the chemokine receptor CCR7 enables

efficient receptor recycling and cell migration. J Cell Sci. 2012;125:4463–74. CAS  PubMed  Google Scholar  * Laufer JM, Hauser MA, Kindinger I, Purvanov V, Pauli A, Legler DF. Chemokine

receptor CCR7 triggers an endomembrane signaling complex for spatial Rac activation. Cell Rep. 2019;29:995–1009. Article  CAS  PubMed  Google Scholar  * Kiermaier E, Moussion C, Veldkamp CT,

Gerardy-Schahn R, de Vries I, Williams LG, et al. Polysialylation controls dendritic cell trafficking by regulating chemokine recognition. Science. 2016;351:186–90. Article  CAS  PubMed 

Google Scholar  * Liu J, Qian C, Cao X. Post-translational modification control of innate immunity. Immunity. 2016;45:15–30. Article  PubMed  CAS  Google Scholar  * Alvarez-Errico D,

Vento-Tormo R, Sieweke M, Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol. 2015;15:7–17. Article  CAS  PubMed  Google Scholar  * Zhang

Q, Cao X. Epigenetic Remodeling in Innate Immunity and Inflammation. Annu Rev Immunol. 2021;39:279–311. * Moran TP, Nakano H, Kondilis-Mangum HD, Wade PA, Cook DN. Epigenetic control of

Ccr7 expression in distinct lineages of lung dendritic cells. J Immunol. 2014;193:4904–13. Article  CAS  PubMed  Google Scholar  * Schliehe C, Flynn EK, Vilagos B, Richson U, Swaminanthan S,

Bosnjak B, et al. The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection. Nat Immunol. 2015;16:67–74. Article  CAS  PubMed  Google Scholar  * Ferrara

G, Benzi A, Sturla L, Marubbi D, Frumento D, Spinelli S, et al. Sirt6 inhibition delays the onset of experimental autoimmune encephalomyelitis by reducing dendritic cell migration. J

Neuroinflammation. 2020;17:228. Article  CAS  PubMed  PubMed Central  Google Scholar  * Fang H, Wu Y, Huang X, Wang W, Ang B, Cao X, et al. Toll-like receptor 4 (TLR4) is essential for

Hsp70-like protein 1 (HSP70L1) to activate dendritic cells and induce Th1 response. J Biol Chem. 2011;286:30393–400. Article  CAS  PubMed  PubMed Central  Google Scholar  * Liu S, Yi L, Ling

M, Jiang J, Song L, Liu J, et al. HSP70L1-mediated intracellular priming of dendritic cell vaccination induces more potent CTL response against cancer. Cell Mol. Immunol. 2018;15:135–45.

Article  CAS  PubMed  Google Scholar  * Yi L, Li Z, Hu T, Liu J, Li N, Cao X, et al. Intracellular HSP70L1 inhibits human dendritic cell maturation by promoting suppressive H3K27me3 and

H2AK119Ub1 histone modifications. Cell Mol Immunol. 2020;17:85–94. Article  CAS  PubMed  Google Scholar  * Turner M, Galloway A, Vigorito E. Noncoding RNA and its associated proteins as

regulatory elements of the immune system. Nat Immunol. 2014;15:484–91. Article  CAS  PubMed  Google Scholar  * Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S, et al. The STAT3-binding long

noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014;344:310–3. Article  CAS  PubMed  Google Scholar  * Xing Z, Lin A, Li C, Liang K, Wang S, Liu Y, et al.

lncRNA directs cooperative epigenetic regulation downstream of chemokine signals. Cell. 2014;159:1110–25. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang H, Hu X, Huang M, Liu

J, Gu Y, Ma L, et al. Mettl3-mediated mRNA m(6)A methylation promotes dendritic cell activation. Nat Commun. 2019;10:1898. Article  PubMed  PubMed Central  CAS  Google Scholar  * Kaelin WG

Jr., McKnight SL. Influence of metabolism on epigenetics and disease. Cell. 2013;153:56–69. Article  CAS  PubMed  PubMed Central  Google Scholar  * Pearce EJ, Everts B. Dendritic cell

metabolism. Nat Rev Immunol. 2015;15:18–29. Article  CAS  PubMed  PubMed Central  Google Scholar  * Westerterp M, Gautier EL, Ganda A, Molusky MM, Wang W, Fotakis P, et al. Cholesterol

accumulation in dendritic cells links the inflammasome to acquired immunity. Cell Metab. 2017;25:1294–304. Article  CAS  PubMed  PubMed Central  Google Scholar  * Tiniakou I, Drakos E,

Sinatkas V, Van Eck M, Zannis VI, Boumpas D, et al. High-density lipoprotein attenuates Th1 and th17 autoimmune responses by modulating dendritic cell maturation and function. J Immunol.

2015;194:4676–87. Article  CAS  PubMed  Google Scholar  * Lühr JJ, Alex N, Amon L, Kräter M, Kubánková M, Sezgin E, et al. Maturation of monocyte-derived DCs leads to increased cellular

stiffness, higher membrane fluidity, and changed lipid composition. Front Immunol. 2020;11:590121. Article  PubMed  PubMed Central  CAS  Google Scholar  * Sawada Y, Honda T, Hanakawa S,

Nakamizo S, Murata T, Ueharaguchi-Tanada Y, et al. Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses. J Exp Med. 2015;212:1921–30.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, et al. Toll-like receptor-induced changes in glycolytic metabolism

regulate dendritic cell activation. Blood. 2010;115:4742–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, et al. TLR-driven

early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat Immunol. 2014;15:323–32. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Guak H, Al Habyan S, Ma EH, Aldossary H, Al-Masri M, Won SY, et al. Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration. Nat

Commun. 2018;9:2463. Article  PubMed  PubMed Central  CAS  Google Scholar  * Moreau HD, Piel M, Voituriez R, Lennon-Dumenil AM. Integrating physical and molecular insights on immune cell

migration. Trends Immunol. 2018;39:632–43. Article  CAS  PubMed  Google Scholar  * Lämmermann T, Renkawitz J, Wu X, Hirsch K, Brakebusch C, Sixt M. Cdc42-dependent leading edge coordination

is essential for interstitial dendritic cell migration. Blood. 2009;113:5703–10. Article  PubMed  CAS  Google Scholar  * Harada Y, Tanaka Y, Terasawa M, Pieczyk M, Habiro K, Katakai T, et

al. DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses. Blood. 2012;119:4451–61. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Krishnaswamy JK, Singh A, Gowthaman U, Wu R, Gorrepati P, Sales Nascimento M, et al. Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic

cell migration. Proc Natl Acad Sci USA. 2015;112:3056–61. Article  CAS  PubMed  PubMed Central  Google Scholar  * Randall KL, Lambe T, Johnson AL, Treanor B, Kucharska E, Domaschenz H, et

al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nat Immunol. 2009;10:1283–91. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Gunawan M, Venkatesan N, Loh JT, Wong JF, Berger H, Neo WH, et al. The methyltransferase Ezh2 controls cell adhesion and migration through direct methylation of the extranuclear

regulatory protein talin. Nat Immunol. 2015;16:505–16. Article  CAS  PubMed  Google Scholar  * Fayngerts SA, Wang Z, Zamani A, Sun H, Boggs AE, Porturas TP, et al. Direction of leukocyte

polarization and migration by the phosphoinositide-transfer protein TIPE2. Nat Immunol. 2017;18:1353–60. Article  CAS  PubMed  PubMed Central  Google Scholar  * de Winde CM, Munday C, Acton

SE. Molecular mechanisms of dendritic cell migration in immunity and cancer. Med Microbiol Immunol. 2020;209:515–29. Article  PubMed  PubMed Central  Google Scholar  * Vargas P, Maiuri P,

Bretou M, Sáez PJ, Pierobon P, Maurin M, et al. Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells. Nat Cell Biol. 2016;18:43–53. Article  CAS

  PubMed  Google Scholar  * Bretou M, Sáez PJ, Sanséau D, Maurin M, Lankar D, Chabaud M, et al. Lysosome signaling controls the migration of dendritic cells. Sci Immunol. 2017;2:eaak9573

(1-11). * Coutant F, Miossec P. Altered dendritic cell functions in autoimmune diseases: distinct and overlapping profiles. Nat Rev Rheumatol. 2016;12:703–15. Article  CAS  PubMed  Google

Scholar  * Miyabe Y, Lian J, Miyabe C, Luster AD. Chemokines in rheumatic diseases: pathogenic role and therapeutic implications. Nat Rev Rheumatol. 2019;15:731–46. Article  PubMed  Google

Scholar  * Han Y, Li X, Zhou Q, Jie H, Lao X, Han J, et al. FTY720 Abrogates collagen-induced arthritis by hindering dendritic cell migration to local lymph nodes. J Immunol.

2015;195:4126–35. Article  CAS  PubMed  Google Scholar  * Moschovakis GL, Bubke A, Friedrichsen M, Ristenpart J, Back JW, Falk CS, et al. The chemokine receptor CCR7 is a promising target

for rheumatoid arthritis therapy. Cell Mol Immunol. 2019;16:791–9. Article  CAS  PubMed  Google Scholar  * He J, Li X, Zhuang J, Han J, Luo G, Yang F, et al. Blocking matrix

metalloproteinase-9 abrogates collagen-induced arthritis via inhibiting dendritic cell migration. J Immunol. 2018;201:3514–23. Article  CAS  PubMed  Google Scholar  * Cao X. COVID-19:

immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20:269–70. Article  CAS  PubMed  PubMed Central  Google Scholar  * Merad M, Martin JC. Pathological inflammation in

patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20:355–62. Article  CAS  PubMed  PubMed Central  Google Scholar  * Zhou R, To KK, Wong YC, Liu L, Zhou

B, Li X, et al. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunity. 2020;53:864–77. Article  CAS  PubMed  PubMed Central  Google Scholar  * Blanco-Melo D,

Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181:1036–45.e1039. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Liao M, Liu Y, Yuan J, Wen Y, Xu G, Zhao J, et al. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med. 2020;26:842–4.

Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by grants from the National Natural Science Foundation of China (32070903, 31870909, and

81788101). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China Juan

Liu, Xiaomin Zhang, Yujie Cheng & Xuetao Cao * Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing,

China Xuetao Cao Authors * Juan Liu View author publications You can also search for this author inPubMed Google Scholar * Xiaomin Zhang View author publications You can also search for this

author inPubMed Google Scholar * Yujie Cheng View author publications You can also search for this author inPubMed Google Scholar * Xuetao Cao View author publications You can also search

for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Juan Liu or Xuetao Cao. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests.

RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Liu, J., Zhang, X., Cheng, Y. _et al._ Dendritic cell migration in inflammation and immunity. _Cell Mol

Immunol_ 18, 2461–2471 (2021). https://doi.org/10.1038/s41423-021-00726-4 Download citation * Received: 03 May 2021 * Accepted: 09 June 2021 * Published: 23 July 2021 * Issue Date: November

2021 * DOI: https://doi.org/10.1038/s41423-021-00726-4 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable

link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * dendritic cells * cell migration *

chemokine receptor CCR7 * inflammation * autoimmune diseases