Skip to main content

Advertisement

Log in

Cell-autonomous and environmental contributions to the interstitial migration of T cells

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

A key to understanding the functioning of the immune system is to define the mechanisms that facilitate directed lymphocyte migration to and within tissues. The recent development of improved imaging technologies, most prominently multi-photon microscopy, has enabled the dynamic visualization of immune cells in real-time directly within intact tissues. Intravital imaging approaches have revealed high spontaneous migratory activity of T cells in secondary lymphoid organs and inflamed tissues. Experimental evidence points towards both environmental and cell-intrinsic cues involved in the regulation of lymphocyte motility in the interstitial space. Based on these data, several conceptually distinct models have been proposed in order to explain the coordination of lymphocyte migration both at the single cell and population level. These range from “stochastic” models, where chance is the major driving force, to “deterministic” models, where the architecture of the microenvironment dictates the migratory trajectory of cells. In this review, we focus on recent advances in understanding naïve and effector T cell migration in vivo. In addition, we discuss some of the contradictory experimental findings in the context of theoretical models of migrating leukocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Alstergren P, Zhu B, Glogauer M, Mak TW, Ellen RP, Sodek J (2004) Polarization and directed migration of murine neutrophils is dependent on cell surface expression of CD44. Cell Immunol 231:146–157

    Article  PubMed  CAS  Google Scholar 

  2. Ansel KM, Cyster JG (2001) Chemokines in lymphopoiesis and lymphoid organ development. Curr Opin Immunol 13:172–179

    Article  PubMed  CAS  Google Scholar 

  3. Asperti-Boursin F, Real E, Bismuth G, Trautmann A, Donnadieu E (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 

  4. Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN (2006) Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25:989–1001

    Article  PubMed  CAS  Google Scholar 

  5. Bartholomaus I, Kawakami N, Odoardi F, Schlager C, Miljkovic D, Ellwart JW, Klinkert WE, Flugel-Koch C, Issekutz TB, Wekerle H et al (2009) Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462:94–98

    Article  PubMed  Google Scholar 

  6. Beltman JB, Maree AF, Lynch JN, Miller MJ, de Boer RJ (2007) Lymph node topology dictates T cell migration behavior. J Exp Med 204:771–780

    Article  PubMed  CAS  Google Scholar 

  7. Berg HC (1993) Random walks in biology. Princeton University Press, Princeton

    Google Scholar 

  8. Boissonnas A, Fetler L, Zeelenberg IS, Hugues S, Amigorena S (2007) In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J Exp Med 204:345–356

    Article  PubMed  CAS  Google Scholar 

  9. Bousso P (2008) T-cell activation by dendritic cells in the lymph node: lessons from the movies. Nat Rev Immunol 8:675–684

    Article  PubMed  CAS  Google Scholar 

  10. Bousso P, Robey E (2003) Dynamics of CD8+ T cell priming by dendritic cells in intact lymph nodes. Nat Immunol 4:579–585

    Article  PubMed  CAS  Google Scholar 

  11. Breart B, Lemaitre F, Celli S, Bousso P (2008) Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J Clin Invest 118:1390–1397

    Article  PubMed  CAS  Google Scholar 

  12. Bretscher A, Edwards K, Fehon RG (2002) ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 3:586–599

    Article  PubMed  CAS  Google Scholar 

  13. 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 

  14. Castellino F, Huang AY, Altan-Bonnet G, Stoll S, Scheinecker C, Germain RN (2006) Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 440:890–895

    Article  PubMed  CAS  Google Scholar 

  15. Cavanagh LL, Weninger W (2008) Dendritic cell behaviour in vivo: lessons learned from intravital two-photon microscopy. Immunol Cell Biol 86:428–438

    Article  PubMed  CAS  Google Scholar 

  16. Chakraborty AK, Dustin ML, Shaw AS (2003) In silico models for cellular and molecular immunology: successes, promises and challenges. Nat Immunol 4:933–936

    Article  PubMed  CAS  Google Scholar 

  17. Chang TW, Celis E, Eisen HN, Solomon F (1979) Crawling movements of lymphocytes on and beneath fibroblasts in culture. Proc Natl Acad Sci USA 76:2917–2921

    Article  PubMed  CAS  Google Scholar 

  18. Chtanova T, Han SJ, Schaeffer M, van Dooren GG, Herzmark P, Striepen B, Robey EA (2009) Dynamics of T cell, antigen-presenting cell, and pathogen interactions during recall responses in the lymph node. Immunity 31:342–355

    Article  PubMed  CAS  Google Scholar 

  19. 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 

  20. Fischer UB, Jacovetty EL, Medeiros RB, Goudy BD, Zell T, Swanson JB, Lorenz E, Shimizu Y, Miller MJ, Khoruts A 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  CAS  Google Scholar 

  21. Forster R, Davalos-Misslitz AC, Rot A (2008) CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 8:362–371

    Article  PubMed  Google Scholar 

  22. Friedl P, Borgmann S, Brocker EB (2001) Amoeboid leukocyte crawling through extracellular matrix: lessons from the Dictyostelium paradigm of cell movement. J Leukoc Biol 70:491–509

    PubMed  CAS  Google Scholar 

  23. Friedl P, Entschladen F, Conrad C, Niggemann B, Zanker KS (1998) CD4+ T lymphocytes migrating in three-dimensional collagen lattices lack focal adhesions and utilize beta1 integrin-independent strategies for polarization, interaction with collagen fibers and locomotion. Eur J Immunol 28:2331–2343

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  25. Friedl P, Wolf K, von Andrian UH, and Harms G (2007) Biological second and third harmonic generation microscopy. Curr Protoc Cell Biol Chapter 4, Unit 4 15

  26. Friedman RS, Jacobelli J, Krummel MF (2006) Surface-bound chemokines capture and prime T cells for synapse formation. Nat Immunol 7:1101–1108

    Article  PubMed  CAS  Google Scholar 

  27. Gail MH, Boone CW (1970) The locomotion of mouse fibroblasts in tissue culture. Biophys J 10:980–993

    Article  PubMed  CAS  Google Scholar 

  28. Germain RN, Miller MJ, Dustin ML, Nussenzweig MC (2006) Dynamic imaging of the immune system: progress, pitfalls and promise. Nat Rev Immunol 6:497–507

    Article  PubMed  CAS  Google Scholar 

  29. Graham DB, Zinselmeyer BH, Mascarenhas F, Delgado R, Miller MJ, Swat W (2009) ITAM signaling by Vav family Rho guanine nucleotide exchange factors regulates interstitial transit rates of neutrophils in vivo. PLoS ONE 4:e4652

    Article  PubMed  Google Scholar 

  30. Huang JH, Cardenas-Navia LI, Caldwell CC, Plumb TJ, Radu CG, Rocha PN, Wilder T, Bromberg JS, Cronstein BN, Sitkovsky M et al (2007) Requirements for T lymphocyte migration in explanted lymph nodes. J Immunol 178:7747–7755

    PubMed  CAS  Google Scholar 

  31. Humbert PO, Dow LE, Russell SM (2006) The Scribble and Par complexes in polarity and migration: friends or foes? Trends Cell Biol 16:622–630

    Article  PubMed  CAS  Google Scholar 

  32. Iparraguirre A, Weninger W (2003) Visualizing T cell migration in vivo. Int Arch Allergy Immunol 132:277–293

    Article  PubMed  Google Scholar 

  33. Jacobelli J, Bennett FC, Pandurangi P, Tooley AJ, Krummel MF (2009) Myosin-IIA and ICAM-1 regulate the interchange between two distinct modes of T cell migration. J Immunol 182:2041–2050

    Article  PubMed  CAS  Google Scholar 

  34. John B, Harris TH, Tait ED, Wilson EH, Gregg B, Ng LG, Mrass P, Roos DS, Dzierszinski F, Weninger W et al (2009) Dynamic Imaging of CD8(+) T cells and dendritic cells during infection with Toxoplasma gondii. PLoS Pathog 5:e1000505

    Article  PubMed  Google Scholar 

  35. Kawakami N, Nagerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flugel A (2005) Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion. J Exp Med 201:1805–1814

    Article  PubMed  CAS  Google Scholar 

  36. Kay RR, Langridge P, Traynor D, Hoeller O (2008) Changing directions in the study of chemotaxis. Nat Rev Mol Cell Biol 9:455–463

    Article  PubMed  CAS  Google Scholar 

  37. Keren K, Pincus Z, Allen GM, Barnhart EL, Marriott G, Mogilner A, Theriot JA (2008) Mechanism of shape determination in motile cells. Nature 453:475–480

    Article  PubMed  CAS  Google Scholar 

  38. Kim JV, Kang SS, Dustin ML, McGavern DB (2009) Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457:191–195

    Article  PubMed  CAS  Google Scholar 

  39. Kowalczyk DW, Wlazlo AP, Blaszczyk-Thurin M, Xiang ZQ, Giles-Davis W, Ertl HC (2001) A method that allows easy characterization of tumor-infiltrating lymphocytes. J Immunol Meth 253:163–175

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Lammermann T, Bader BL, Monkley SJ, Worbs T, Wedlich-Soldner R, Hirsch K, Keller M, Forster R, Critchley DR, Fassler R et al (2008) Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453:51–55

    Article  PubMed  Google Scholar 

  42. Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84:359–369

    Article  PubMed  CAS  Google Scholar 

  43. Lee JH, Katakai T, Hara T, Gonda H, Sugai M, Shimizu A (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 

  44. Macara IG (2004) Parsing the polarity code. Nat Rev Mol Cell Biol 5:220–231

    Article  PubMed  CAS  Google Scholar 

  45. Mempel TR, Henrickson SE, Von Andrian UH (2004) T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427:154–159

    Article  PubMed  CAS  Google Scholar 

  46. Mempel TR, Junt T, von Andrian UH (2006) Rulers over randomness: stroma cells guide lymphocyte migration in lymph nodes. Immunity 25:867–869

    Article  PubMed  CAS  Google Scholar 

  47. Miller MJ, Safrina O, Parker I, Cahalan MD (2004) Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J Exp Med 200:847–856

    Article  PubMed  CAS  Google Scholar 

  48. 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 

  49. 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 

  50. Mohler W, Millard AC, Campagnola PJ (2003) Second harmonic generation imaging of endogenous structural proteins. Methods 29:97–109

    Article  PubMed  CAS  Google Scholar 

  51. Mrass P, Kinjyo I, Ng LG, Reiner SL, Pure E, Weninger W (2008) CD44 mediates successful interstitial navigation by killer T cells and enables efficient antitumor immunity. Immunity 29:971–985

    Article  PubMed  CAS  Google Scholar 

  52. Mrass P, Takano H, Ng LG, Daxini S, Lasaro MO, Iparraguirre A, Cavanagh LL, von Andrian UH, Ertl HC, Haydon PG et al (2006) Random migration precedes stable target cell interactions of tumor-infiltrating T cells. J Exp Med 203:2749–2761

    Article  PubMed  CAS  Google Scholar 

  53. Mrass P, Weninger W (2006) Immune cell migration as a means to control immune privilege: lessons from the CNS and tumors. Immunol Rev 213:195–212

    Article  PubMed  Google Scholar 

  54. Muller G, Hopken UE, Lipp M (2003) The impact of CCR7 and CXCR5 on lymphoid organ development and systemic immunity. Immunol Rev 195:117–135

    Article  PubMed  Google Scholar 

  55. Ng LG, Mrass P, Kinjyo I, Reiner SL, Weninger W (2008) Two-photon imaging of effector T-cell behavior: lessons from a tumor model. Immunol Rev 221:147–162

    Article  PubMed  CAS  Google Scholar 

  56. Nombela-Arrieta C, Mempel TR, Soriano SF, Mazo I, Wymann MP, Hirsch E, Martinez AC, Fukui Y, von Andrian UH, Stein JV (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 

  57. Odoardi F, Kawakami N, Klinkert WE, Wekerle H, Flugel A (2007) Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease. Proc Natl Acad Sci USA 104:18625–18630

    Article  PubMed  CAS  Google Scholar 

  58. 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 

  59. Okada T, Miller MJ, Parker I, Krummel MF, Neighbors M, Hartley SB, O'Garra A, Cahalan MD, Cyster JG (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  Google Scholar 

  60. Petrie RJ, Doyle AD, Yamada KM (2009) Random versus directionally persistent cell migration. Nat Rev Mol Cell Biol 10:538–549

    Article  PubMed  CAS  Google Scholar 

  61. Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45

    Article  PubMed  CAS  Google Scholar 

  62. Pure E, Cuff CA (2001) A crucial role for CD44 in inflammation. Trends Mol Med 7:213–221

    Article  PubMed  CAS  Google Scholar 

  63. Renkawitz J, Schumann K, Weber M, Lammermann T, Pflicke H, Piel M, Polleux J, Spatz JP, Sixt M (2009) Adaptive force transmission in amoeboid cell migration. Nat Cell Biol 11:1438–1443

    Article  PubMed  CAS  Google Scholar 

  64. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR (2003) Cell migration: integrating signals from front to back. Science 302:1704–1709

    Article  PubMed  CAS  Google Scholar 

  65. Riggs T, Walts A, Perry N, Bickle L, Lynch JN, Myers A, Flynn J, Linderman JJ, Miller MJ, Kirschner DE (2008) A comparison of random vs. chemotaxis-driven contacts of T cells with dendritic cells during repertoire scanning. J Theor Biol 250:732–751

    Article  PubMed  CAS  Google Scholar 

  66. Samadani A, Mettetal J, van Oudenaarden A (2006) Cellular asymmetry and individuality in directional sensing. Proc Natl Acad Sci USA 103:11549–11554

    Article  PubMed  CAS  Google Scholar 

  67. Shakhar G, Lindquist RL, Skokos D, Dudziak D, Huang JH, Nussenzweig MC, Dustin ML (2005) Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo. Nat Immunol 6:707–714

    Article  PubMed  CAS  Google Scholar 

  68. Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76:301–314

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  70. von Andrian UH, Mackay CR (2000) T-cell function and migration. Two sides of the same coin. N Engl J Med 343:1020–1034

    Article  Google Scholar 

  71. 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 

  72. Weninger W, von Andrian UH (2003) Chemokine regulation of naive T cell traffic in health and disease. Semin Immunol 15:257–270

    Article  PubMed  CAS  Google Scholar 

  73. Wilson EH, Harris TH, Mrass P, John B, Tait ED, Wu GF, Pepper M, Wherry EJ, Dzierzinski F, Roos D et al (2009) Behavior of parasite-specific effector CD8+ T cells in the brain and visualization of a kinesis-associated system of reticular fibers. Immunity 30:300–311

    Article  PubMed  CAS  Google Scholar 

  74. Witt C, Raychaudhuri S, Chakraborty AK (2005) Movies, measurement, and modeling: the three Ms of mechanistic immunology. J Exp Med 201:501–504

    Article  PubMed  CAS  Google Scholar 

  75. Woolf E, Grigorova I, Sagiv A, Grabovsky V, Feigelson SW, Shulman Z, Hartmann T, Sixt M, Cyster JG, Alon R (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 

  76. 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 

  77. Worbs T, Mempel TR, Bolter J, von Andrian UH, Forster R (2007) CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo. J Exp Med 204:489–495

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Drs. Ichiko Kinjyo, Sioh-Yang Tan, Lois Cavanagh, Ben Roediger, Nital Sumaria, and Saparna Pai for critical reading of the manuscript. This work was supported by grants from the NHMRC and the New South Wales Cancer Institute. P.M. is recipient of the Career Development and Support Fellowship, Cancer Institute, New South Wales.

Open Access

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Paulus Mrass or Wolfgang Weninger.

Additional information

This article is published as part of the Special Issue on Immunoimaging of Immune System Function.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mrass, P., Petravic, J., Davenport, M.P. et al. Cell-autonomous and environmental contributions to the interstitial migration of T cells. Semin Immunopathol 32, 257–274 (2010). https://doi.org/10.1007/s00281-010-0212-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-010-0212-1

Keywords

Navigation