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Chemoattract Receptor Signaling and Its Role in Lymphocyte Motility and Trafficking

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Visualizing Immunity

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 334))

Abstract

Intravital microscopy has provided extraordinary glimpses of lymphocytes crossing high endothelial venules, detailed the movements and interactions of lymphocytes within lymph organs, and recorded lymphocytes crossing the lymphatic endothelium into the efferent lymph. Helping to orchestrate these movements are signals generated by the engagement of chemoattractants with their cognate receptors. Chemokines present on high endothelial venules and within lymph organs, and the high levels of sphingosine 1-phosphate in the lymph provide signposts to help guide lymphocytes and provide intracellular signals that affect lymphocyte polarity and motility. Within lymph nodes, T and B lymphocytes migrate along networks of fibroblastic reticular cells and follicular dendritic, respectively, which provide an adhesive platform and solid phased chemokines. Illustrating the importance of chemoattractant receptors in these processes, lymphocytes that lack CXCR4, CXCR5, CCR7, or S1PR1, or which lack crucial signaling molecules activated by these receptors, exhibit defects in lymph node entrance, positioning, polarity, motility, and/or lymph node egress. This review will focus on the contributions of in vivo imaging of lymphocytes from various mouse mutants to our understanding of the roles chemoattractants play in lymphocyte entrance into and exit from lymph nodes, and in coordinating and facilitating the movements of lymphocytes within lymph nodes.

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References

  • Allen CD, Okada T, Tang HL et al (2007) Imaging of germinal center selection events during affinity maturation. Science 315:528–531

    Article  PubMed  CAS  Google Scholar 

  • Ansel KM, Ngo VN, Hyman PL et al (2000) A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406:309–314

    Article  PubMed  CAS  Google Scholar 

  • Arai H, Tsou CL, Charo IF (1997) Chemotaxis in a lymphocyte cell line transfected with C-C chemokine receptor 2B: evidence that directed migration is mediated by betagamma dimers released by activation of Galphai-coupled receptors. Proc Natl Acad Sci USA 94:14495–14499

    Article  PubMed  CAS  Google Scholar 

  • Asperti-Boursin F, Real E, Bismuth G et al (2007) CCR7 ligands control basal T-cell motility within lymph node slices in a phosphoinositide 3-kinase-independent manner. J Exp Med 204:1167–1179

    Article  PubMed  CAS  Google Scholar 

  • Bajenoff M, Egen JG, Koo LY, et al (2006) Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25:989–1001

    Article  PubMed  CAS  Google Scholar 

  • Bardi G, Niggli V, Loetscher P (2003) Rho kinase is required for CCR7-mediated polarization and chemotaxis of T lymphocytes. FEBS Lett 542:79–83

    Article  PubMed  CAS  Google Scholar 

  • Bromley SK, Mempel TR, Luster AD (2008) Orchestrating the orchestrators: chemokines in control of T-cell traffic. Nat Immunol 9:970–980

    Article  PubMed  CAS  Google Scholar 

  • Burkhardt JK, Carrizosa E, Shaffer MH (2008) The actin cytoskeleton in T-cell activation. Annu Review Immunol 26:233–259

    Article  CAS  Google Scholar 

  • Cahalan MD, Parker I (2008) Choreography of cell motility and interaction dynamics imaged by two-photon microscopy in lymphoid organs. Annu Rev Immunol 26:585–626

    Article  PubMed  CAS  Google Scholar 

  • Croker BA, Tarlinton DM, Cluse LA et al (2002) The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes. J Immunol 168:3376–3386

    PubMed  CAS  Google Scholar 

  • Cyster JG (2005) Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 23:127–159

    Article  PubMed  CAS  Google Scholar 

  • Doupnik CA, Davidson N, Lester HA, Kofuji P (1997) RGS proteins reconstitute the rapid gating kinetics of gbetagamma-activated inwardly rectifying K+ channels. Proc Natl Acad Sci USA 94:10461–10466

    Article  PubMed  CAS  Google Scholar 

  • Druey KM, Blumer KJ, Kang VH, Kehrl JH (1996) Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family. Nature 379:742–746

    Article  PubMed  CAS  Google Scholar 

  • Fischer UB, Jacovetty EL, Medeiros RB et al (2007) MHC class II deprivation impairs CD4 T-cell motility and responsiveness to antigen-bearing dendritic cells in vivo. Proc Natl Acad Sci USA 104:7181–7186

    Article  PubMed  Google Scholar 

  • Forster R, Mattis AE, Kremmer E et al (1996) A putative chemokine receptor, BLR1, directs B-cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 871037–1047

    Google Scholar 

  • Forster R, Schubel A, Breitfeld D et al (1999) CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99:23–33

    Article  PubMed  CAS  Google Scholar 

  • Friedl P, Weigelin B (2008) Interstitial leukocyte migration and immune function. Nat Immunol 9:960–969

    Article  PubMed  CAS  Google Scholar 

  • Fukui Y, Hashimoto O, Sanui T et al (2001) Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 412:826–831

    Article  PubMed  CAS  Google Scholar 

  • Gallego MD, de la Fuente MA, Anton IM et al (2006) WIP and WASP play complementary roles in T-cell homing and chemotaxis to SDF-1alpha. Int Immunol 18:221–232

    Article  PubMed  CAS  Google Scholar 

  • Gerard A, Mertens AE, van der Kammen RA, Collard JG (2007) The Par polarity complex regulates Rap1- and chemokine-induced T-cell polarization. J Cell Biol 176(6):863–875

    Article  PubMed  CAS  Google Scholar 

  • Goley ED, Welch MD (2006) The ARP2/3 complex: an actin nucleator comes of age. Nat Rev Mol Cell Biol 7:713–726

    Article  PubMed  CAS  Google Scholar 

  • Gretz JE, Norbury CC, Anderson AO et al (2000) 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 microenvironments in lymph node cortex. J Exp Med 192:1425–1440

    Article  PubMed  CAS  Google Scholar 

  • Gunn MD, Ngo VN, Ansel KM et al (1998) A B-cell-homing chemokine made in lymphoid follicles activates Burkitt’s lymphoma receptor-1. Nature 391:799–803

    Article  PubMed  CAS  Google Scholar 

  • Haddad E, Zugaza JL, Louache F et al (2001) The interaction between Cdc42 and WASP is required for SDF-1-induced T-lymphocyte chemotaxis. Blood 97:33–38

    Article  PubMed  CAS  Google Scholar 

  • Han SB, Moratz C, Huang NN et al (2005) Rgs1 and Gnai2 regulate the entrance of B lymphocytes into lymph nodes and B-cell motility within lymph node follicles. Immunity 22:343–354

    Article  PubMed  CAS  Google Scholar 

  • Hauser AE, Junt T, Mempel TR et al (2007) Definition of germinal-center B-cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26:655–667

    Article  PubMed  CAS  Google Scholar 

  • Hirsch E, Katanaev VL, Garlanda C et al (2000) Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287:1049–1053

    Article  PubMed  CAS  Google Scholar 

  • Huang JH, Cardenas-Navia LI et al (2007) Requirements for T lymphocyte migration in explanted lymph nodes. J Immunol 178:7747–7755

    PubMed  CAS  Google Scholar 

  • Hwang IY, Park C, Kehrl JH (2007) Impaired trafficking of Gnai2+/- and Gnai2-/- T lymphocytes: implications for T-cell movement within lymph nodes. J Immunol 179:439–448

    PubMed  CAS  Google Scholar 

  • Jacobelli J, Chmura SA, Buxton DB et al (2004) A single class II myosin modulates T-cell motility and stopping, but not synapse formation. Nat Immunol 5:531–538

    Article  PubMed  CAS  Google Scholar 

  • Kanemitsu N, Ebisuno Y, Tanaka T et al (2005) CXCL13 is an arrest chemokine for B-cells in high endothelial venules. Blood 106:2613–2618

    Article  PubMed  CAS  Google Scholar 

  • Katagiri K, Imamura M, Kinashi T (2006) Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat Immunol 7:919–928

    Article  PubMed  CAS  Google Scholar 

  • Katagiri K, Maeda A, Shimonaka M, Kinashi T (2003) RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat Immunol 4:741–748

    Article  PubMed  CAS  Google Scholar 

  • Katagiri K, Ohnishi N, Kabashima K et al (2004) Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking. Nat Immunol 5:1045–1051

    Article  PubMed  CAS  Google Scholar 

  • Kehrl JH (1998) Heterotrimeric G protein signaling: roles in immune function and fine-tuning by RGS proteins. Immunity 8:1–10

    Article  PubMed  CAS  Google Scholar 

  • Kehrl JH (2004) G-protein-coupled receptor signaling, RGS proteins, and lymphocyte function. Crit Rev Immunol 24:409–423

    Article  PubMed  CAS  Google Scholar 

  • Kinashi T, Katagiri K (2005) Regulation of immune cell adhesion and migration by regulator of adhesion and cell polarization enriched in lymphoid tissues. Immunology 116:164–171

    Article  PubMed  CAS  Google Scholar 

  • Koelle MR, Horvitz HR (1996) EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins. Cell 84:115–125

    Article  PubMed  CAS  Google Scholar 

  • Krummel MF, Macara I (2006) Maintenance and modulation of T-cell polarity. Nat Immunol 7:1143–1149

    Article  PubMed  CAS  Google Scholar 

  • Lammermann T, Bader BL, Monkley SJ et al (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453:51–55

    Article  PubMed  CAS  Google Scholar 

  • Ledgerwood LG, Lal G, Zhang N et al (2008) The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics. Nat Immunol 9:42–53

    Article  PubMed  CAS  Google Scholar 

  • Lee JH, Katakai T, Hara T et al (2004) Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J Cell Biol 167:327–337

    Article  PubMed  CAS  Google Scholar 

  • Li Z, Jiang H, Xie W et al (2000) Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. Science 287:1046–1049

    Article  PubMed  CAS  Google Scholar 

  • Manes S, Gomez-Mouton C, Lacalle RA et al (2005) Mastering time and space: immune cell polarization and chemotaxis. Semin Immunol 17:77–86

    Article  PubMed  CAS  Google Scholar 

  • Matheu MP, Deane JA, Parker I et al (2007) Class IA phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node. J Immunol 179:2261–2269

    PubMed  CAS  Google Scholar 

  • Matloubian M, Lo CG, Cinamon G et al (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–360

    Article  PubMed  CAS  Google Scholar 

  • McVerry BJ, Garcia JG (2005) In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights. Cell Signal 17:131–139

    Article  PubMed  CAS  Google Scholar 

  • Miller MJ, Wei SH, Cahalan MD, Parker I (2003) Autonomous T-cell trafficking examined in vivo with intravital two-photon microscopy. Proc Natl Acad Sci USA 100:2604–2609

    Article  PubMed  CAS  Google Scholar 

  • Miller MJ, Wei SH, Parker I, Cahalan MD (2002) Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296:1869–1873

    Article  PubMed  CAS  Google Scholar 

  • Moratz C, Hayman JR, Gu H, Kehrl JH (2004) Abnormal B-cell responses to chemokines, disturbed plasma cell localization, and distorted immune tissue architecture in Rgs1-/- mice. Mol Cell Biol 24:5767–5775

    Article  PubMed  CAS  Google Scholar 

  • Neer EJ (1995) Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80(2):249–257

    Article  PubMed  CAS  Google Scholar 

  • Neptune ER, Iiri T, Bourne HR (1999) Galphai is not required for chemotaxis mediated by Gi-coupled receptors. J Biol Chem 274:2824–2828

    Article  PubMed  CAS  Google Scholar 

  • Nombela-Arrieta C, Lacalle RA, Montoya MC et al (2004) Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing. Immunity 21:429–441

    Article  PubMed  CAS  Google Scholar 

  • Nombela-Arrieta C, Mempel TR, Soriano SF et al (2007) A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress. J Exp Med 204:497–510

    Article  PubMed  CAS  Google Scholar 

  • Oak JS, Matheu MP, Parker I et al (2007) Lymphocyte cell motility: the twisting, turning tale of phosphoinositide 3-kinase. Biochem Soc Trans 35(Pt 5):1109–1113

    PubMed  CAS  Google Scholar 

  • Offermanns S, Simon MI (1996) Organization of transmembrane signalling by heterotrimeric G proteins. Cancer Surv 27:177–198

    PubMed  CAS  Google Scholar 

  • Okada T, Cyster JG (2007) CC chemokine receptor 7 contributes to Gi-dependent T-cell motility in the lymph node. J Immunol 178:2973–2978

    PubMed  CAS  Google Scholar 

  • Okada T, Miller MJ, Parker I et al (2005) Antigen-engaged B-cells undergo chemotaxis toward the T zone and form motile conjugates with helper T-cells. PLoS Biol 3:e150

    Article  PubMed  CAS  Google Scholar 

  • Okada T, Ngo VM, Ekland EH et al (2002) Chemokine requirements for B-cell entry to lymph nodes and Peyer’s patches. J Exp Med 196:65–75

    Article  PubMed  CAS  Google Scholar 

  • Ortolano S, Hwang IY, Han SB, Kehrl JH (2006) Roles for phosphoinositide 3-kinases, Bruton’s tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing. Eur J Immunol 36:1285–1295

    Article  PubMed  CAS  Google Scholar 

  • Pappu R, Schwab SR, Cornelissen I et al (2007) Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316:295–298

    Article  PubMed  CAS  Google Scholar 

  • Pasvolsky R, Feigelson SW, Kilic SS et al (2007) A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med 204:1571–1582

    PubMed  CAS  Google Scholar 

  • Pham TH, Okada T, Matloubian M et al (2008) S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T-cell egress. Immunity 28:122–133

    Article  PubMed  CAS  Google Scholar 

  • Reif K, Okkenhaug K, Sasaki T et al (2004) Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 173:2236–2240

    PubMed  CAS  Google Scholar 

  • Rosen H, Gonzalez-Cabrera P, Marsolais D et al (2008) Modulating tone: the overture of S1P receptor immunotherapeutics. Immunol Rev 223:221–235

    Article  PubMed  CAS  Google Scholar 

  • Rudolph U, Finegold MJ, Rich SS et al (1995) Ulcerative colitis and adenocarcinoma of the colon in G alpha i2-deficient mice. Nat Genet 10:143–150

    Article  PubMed  CAS  Google Scholar 

  • Sakata D, Taniguchi H, Yasuda S et al (2007) Impaired T lymphocyte trafficking in mice deficient in an actin-nucleating protein, mDia1. J Exp Med 204:2031–2038

    Article  PubMed  CAS  Google Scholar 

  • Sanna MG, Wang SK, Gonzalez-Cabrera PJ et al (2006) Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol 2:434–441

    Article  PubMed  CAS  Google Scholar 

  • Schwickert TA, Lindquist RL, Shakhar G et al (2007) In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446:83–87

    Article  PubMed  CAS  Google Scholar 

  • Shimonaka M, Katagiri K, Nakayama T et al (2003) Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J Cell Biol 161:417–427

    Article  PubMed  CAS  Google Scholar 

  • Snapper SB, Meelu P, Nguyen D et al (2005) WASP deficiency leads to global defects of directed leukocyte migration in vitro and in vivo. J Leukoc Biol 77:993–998

    Article  PubMed  CAS  Google Scholar 

  • Stachowiak AN, Wang Y, Huang YC, Irvine DJ (2006) Homeostatic lymphoid chemokines synergize with adhesion ligands to trigger T and B lymphocyte chemokinesis. J Immunol 177:2340–2348

    PubMed  CAS  Google Scholar 

  • Sumen C, Mempel TR, Mazo IB, von Andrian UH (2004) Intravital microscopy: visualizing immunity in context. Immunity 21:315–329

    PubMed  CAS  Google Scholar 

  • Takesono A, Horai R, Mandai M et al (2004) Requirement for Tec kinases in chemokine-induced migration and activation of Cdc42 and Rac. Curr Biol 14:917–922

    Article  PubMed  CAS  Google Scholar 

  • Thelen M, Stein JV (2008) How chemokines invite leukocytes to dance. Nat Immunol 9:953–959

    Article  PubMed  CAS  Google Scholar 

  • Vicente-Manzanares M, Rey M, Perez-Martinez M et al (2003) The RhoA effector mDia is induced during T-cell activation and regulates actin polymerization and cell migration in T lymphocytes. J Immunol 171:1023–1034

    PubMed  CAS  Google Scholar 

  • von Andrian UH (1996) Intravital microscopy of the peripheral lymph node microcirculation in mice. Microcirculation 3:287–300

    Article  PubMed  CAS  Google Scholar 

  • Wei SH, Parker I, Miller MJ, Cahalan MD (2003) A stochastic view of lymphocyte motility and trafficking within the lymph node. Immunol Rev 195:136–159

    Article  PubMed  CAS  Google Scholar 

  • Wei SH, Rosen H, Matheu MP et al (2005) Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T-cells to lymphatic sinuses. Nat Immunol 6:1228–35

    Article  PubMed  CAS  Google Scholar 

  • Woolf E, Grigorova I, Sagiv A et al (2007) Lymph node chemokines promote sustained T lymphocyte motility without triggering stable integrin adhesiveness in the absence of shear forces. Nat Immunol 8:1076–1085

    Article  PubMed  CAS  Google Scholar 

  • Worbs T, Bernhardt G, Forster R (2008) Factors governing the intranodal migration behavior of T lymphocytes. Immunol Rev 221:44–63

    Article  PubMed  CAS  Google Scholar 

  • Worbs T, Mempel TR, Bolter J et al (2007) CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo. J Exp Med 204:489–495

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are supported by the intramural research program of the National Institute of Allergy and Infectious Diseases.

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Correspondence to John H. Kehrl .

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Kehrl, J. ., Hwang, IY., Park, C. (2009). Chemoattract Receptor Signaling and Its Role in Lymphocyte Motility and Trafficking. In: Dustin, M., McGavern, D. (eds) Visualizing Immunity. Current Topics in Microbiology and Immunology, vol 334. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-93864-4_5

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